the importance of synthetic drugs for type 2 diabetes drug …tums.ac.ir/1392/11/19/expert opin....
TRANSCRIPT
1. Introduction
2. Pathophysiology of T2DM
3. Overview of current synthetic
drugs in the treatment of
T2DM
4. New synthetic compounds as
DPP-4 inhibitors
5. New synthetic compounds as
SGLT2 inhibitors
7. Conclusion
8. Expert opinion
Review
The importance of synthetic drugsfor type 2 diabetes drug discoveryMaliheh Safavi, Alireza Foroumadi & Mohammad Abdollahi†
†Tehran University of Medical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences
Research Center, Tehran, Iran
Introduction: Type 2 diabetes mellitus (T2DM) is a major metabolic,
multi-causal and heterogeneous disorder which causes significant morbid-
ity and mortality with considerable burden to healthcare resources. The
number of deaths due to T2DM highlights the insufficiency of the cur-
rently available drugs for controlling the disease and its complications
and more needs to be done.
Areas covered: This paper reviews the updated pathobiology of T2DM that
should be targeted in drug discovery. Further, the article provides discussion
on the mechanism of action, side effects and structure of the currently avail-
able synthetic drugs. The authors specifically evaluate two newer classes of
anti-diabetic agents: dipeptidyl peptidase IV (DPP-4) and sodium-glucose
transporter-2 (SGLT2). They also present information on newer synthetic com-
pounds. The article also highlights the key interactions between synthetic
compounds and DPP-4 active site residues for rational drug design.
Expert opinion: Numerous anti-hyperglycaemic drugs are currently available
but many are limited by their adverse effects. The identification of the 3D
structure of DPP-4 has opened new avenues for design, thus aiming to pro-
duce drugs that directly exploit the structural characteristics of this binding
site. Further, structural- and ligand-based screening techniques have been
developed for designing novel DPP-4 and SGLT2 inhibitors. There has also
been progress with the design and development of novel T2DM therapeutics
including: PPARa/ dual agonists, Sirtuin 1 activators, glycogen phosphorylase
inhibitors and protein tyrosine phosphatase 1B inhibitors. Finding new tar-
gets and synthesis methods is still essential but it is becoming accepted that
no diabetic therapy is ‘best suited’ with each patient responding differently.
Keywords: anti-diabetic agents, dipeptidyl peptidase IV inhibitors, sodium-glucose transporter-
2 inhibitors, synthetic drugs, type 2 diabetes
Expert Opin. Drug Discov. (2013) 8(11):1339-1363
1. Introduction
Diabetes comprises a group of metabolic disorders characterised by chronichyperglycaemia with disorders in the metabolism of carbohydrate, fat and proteinthat result in defects in secretion and action of insulin [1]. Dysfunction and failureof various organs, especially the eyes, kidneys, nerves, heart and the blood vessels arethe usual complications of diabetes [2,3]. Diabetes is mainly divided into four maintypes including insulin-dependent diabetes mellitus (type 1), non-insulin-depen-dent diabetes mellitus (type 2), gestational diabetes and other specific types [1,4].
Type 2 diabetes mellitus (T2DM) is very common and accounts for ~ 90 -- 95%of all diabetic cases. The worldwide increase in T2DM becomes a most importanthealth concern [5]. T2DM is usually accompanied with insulin resistance in the skel-etal muscles and the liver, and the reduction in insulin production by the pan-creas [6]. Genetic susceptibility and various environmental factors [7,8] are alsoinvolved in T2DM. Patients with T2DM are at risk of vascular complications
10.1517/17460441.2013.837883 © 2013 Informa UK, Ltd. ISSN 1746-0441, e-ISSN 1746-045X 1339All rights reserved: reproduction in whole or in part not permitted
Exp
ert O
pin.
Dru
g D
isco
v. D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Se
rial
s U
nit -
Lib
rary
on
11/0
4/13
For
pers
onal
use
onl
y.
such as coronary artery disease, stroke, hypertension,nephropathy, peripheral vascular disease, neuropathy andretinopathy [9-13]. It has been suggested that higher glucoselevels may be a risk factor for dementia [14]. AlthoughT2DM was traditionally seen in individuals over the age of40, recent data from several countries confirm that T2DMoccurs in younger people even in childhood [15,16]. Cases ofT2DM that occurs before 30 years of age usually develop dia-betic nephropathy, renal failure, blindness and atheroscleroticvascular disease in their 30s [17].Although there are several therapeutic options available for
the management of diabetes, most of them respond only inthe short-to-medium term. Further, most of current therapiesare associated with an increased risk of adverse effects such asweight gain (sulphonylureas, thiazolidinediones and insulin),hypoglycaemia (sulphonylureas and insulin), gastrointestinalintolerance (metformin) and myocardial infarction (rosiglita-zone) [18,19]. Researchers are trying to find therapies betterthan the three oldest classes, for example, insulin, sulphonylur-eas and biguanides but the newer ones have not shown morepotency and were often less effective in lowering glycaemia [19].Alternative to these synthetic agents, new insulin analogues,
inhaled insulin and many medicinal plants are being investi-gated for possible benefits in diabetes [20-30]. Moreover, insu-lin--mimetic complexes have been synthesized in the thoughtthat these complexes affect both diabetes and its complica-tions [31,32]. Of course, concerns of safety and tolerability ofcurrent treatments and the progressive nature of T2DM callfor new classes of medicines. This review provides a discussionof current synthetic pharmacological agents and new syntheticcompounds for T2DM.
2. Pathophysiology of T2DM
Unlike simple characterisation of type 1 diabetes, the patho-genesis of T2DM is more complex and still remains a matterof argument. The most problem is that the specific aetiologies
have not yet been clearly elucidated. For instance, unliketype 1 diabetes, autoimmune destruction of cells does notoccur and ketoacidosis seldom occurs [33]. As mentioned ear-lier, peripheral insulin resistance and b-cell dysfunction arerather involved in T2DM [34]. Insulin resistance and therelated consequences called insulin resistance syndrome(IRS) or the metabolic syndrome are common in T2DM,deemed mainly linking to patients’ genetic background [35].Insulin resistance is also linked to obesity [36], dyslipidemia,hypertension and increased cardiovascular risk [37].
However, risk alleles in some loci seem having a primaryimpact on insulin sensitivity. Peroxisome proliferator-activated receptor-g (PPAR-g), glucokinase regulator andinsulin-like growth factor 1 have been proved as insulin resis-tance locus from T2DM susceptibility loci [38]. Obesity andlifestyle are independent risk factor for T2DM [1,39]. Accord-ing to short-term studies, numerous benefits of weight losscan be achieved in overweight or obese patients withT2DM. The finding of recent study indicated that the inten-sive lifestyle intervention do not reduce the rate of cardiovas-cular morbidity and mortality in overweight or obese patientswith T2DM [40]. Gastric bypass induces substantial and sus-tained weight loss and is a highly effective treatment forobesity-related diabetes. Laboratory data suggest that gastricbypass exhibits reprogramming of intestinal glucose metabo-lism which renders the intestine a major tissue for glucose dis-posal, contributing to the improvement in glycaemic controlafter surgery [41].
Several studies have indicated that obesity correlates with alow-grade inflammation of the white adipose tissue. Thisresults from activation of some pro-inflammatory signallingpathways which end up with insulin resistance, impaired glu-cose tolerance and diabetes [39,42]. Recent data indicate thatwhite adipose tissue in obese patients is infiltrated by macro-phages [43]. Several pro-inflammatory factors, such asTNF-a and IL-6, are derived not only from adipocytes butalso from infiltrated macrophages [39]. The role of cytokinesand insulin signalling pathways should not be missed as thisinteraction results in change of insulin action [44,45]. Nor-mally, insulin acts through binding to and activation of itscell-surface receptors. Such receptors are made up of two asubunits and two b subunits, which are disulfide linkedinto a2b2 heterotetrameric complex. The actions of insulinare initiated when the receptor is bound to the extracellulara subunits, causing phosphorylation of intracellular tyrosinekinase domain of the b subunits and inducing a con-formational change [46-48]. Phosphorylation of the insulinreceptor can activate insulin receptor substrate complexes(IRS-1 -- IRS-4). The activated IRS binds to the p85 regula-tory subunit of phosphatidylinositol (PI) 3-kinase that resultsin activation of p110 catalytic subunit [47,49,50]. PI(3,4,5)P3 which is produced by enzymatic activity of PI3-kinase isa key lipid second messenger in various metabolic effects ofinsulin [51]. PI (3,4,5)P3 mediates the signal transduction todownstream molecules including Akt and atypical protein
Article highlights.
. The incidence of T2DM continues to grow rapidlyworldwide and is associated with multiple comorbidities.
. Peripheral insulin resistance and b-cell failure representthe core pathophysiological defects in T2DM.
. Currently available synthetic drug therapies includemetformin, sulphonylurea and other insulinsecretagogues, thiazolidinediones, a-glucosidaseinhibitors, GLP1 agonists, dopamine-2 agonists, bile acidsequestrants, DPP-4 and SGLT2 inhibitors.
. Two latter classes (DPP-4 and SGLT2 inhibitors) are noveland promising drugs that target novel mechanisms.
. Finding new drug targets and new faster and cheapersynthesis methods are the main goals of T2DMdrug discovery.
This box summarises key points contained in the article.
M. Safavi et al.
1340 Expert Opin. Drug Discov. (2013) 8(11)
Exp
ert O
pin.
Dru
g D
isco
v. D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Se
rial
s U
nit -
Lib
rary
on
11/0
4/13
For
pers
onal
use
onl
y.
kinase C. These are the key signalling molecules in the activa-tion of glucose uptake, inhibition of apoptosis and synthesisof proteins [49,52-54].
It is thought that in adipose and retinal tissues, phosphory-lation on specific serine sites (Ser307) on IRS-1 reducesthe tyrosine phosphorylation of the insulin receptor [48,55].The cytokine TNF-a plays a major role through phosphory-lation of the IRS-1 protein on Ser307 site. TNF-a-inducedinhibition of IRS-1 signalling can reduce Akt phosphorylationand stop the insulin signalling pathway [39,48]. Also, it hasbeen shown that TNF-a causes marked downregulation ofthe adipocytes and muscle cells insulin-regulable glucosetransporter [56].
According to recent studies, the circulating IL-6 correlateswith insulin sensitivity in obese humans [57]. This meansthat both TNF- a and IL-6 and other adipocyte-specific sig-nalling elements such as resistin and leptin can alter insulinsensitivity by provoking diverse key steps in the process ofinsulin action [36,58]. Any defect in insulin action or the IRStriggers b-cells in a way to cause T2DM [59]. The interplaybetween insulin resistance and b-cell dysfunction remainshighly complex [60]. Studies of insulin-resistant animals illus-trate an important role for expansion of the b-cell mass andenhanced b-cell function as the compensatory mecha-nisms [61]. In most obese and insulin-resistant individuals,b-cell compensation reduces due to hyperglycaemia and lipidtoxicity [62,63]. Continuous decline of b-cell function usually
ends up in b-cell exhaustion and finally b-cell failure anddiabetes [60].
Numerous studies have demonstrated that enhanced pro-inflammatory cytokines, free radicals and oxidative stress are cen-tral events to the development of diabetic complications [13,64-66].Dominant cause of oxidative stress in diabetes is glucose autoxi-dation that leads to production of free radicals [67]. Oxidativestress causes b-cell death via induction of mitochondrial stressduring development of diabetes. In pancreatic b cells, importanttargets for an oxidant insult are ATP-dependent potassium(KATP) channels and cell metabolism [68]. The efficacies of dif-ferent approaches in the reduction of diabetes-induced oxidativestress have been studied and usage of antioxidants as thesupplement to drug regimen of T2DM patients has beenrecommended [69-79]. Briefly, the pathobiology of T2DM whichare considered as targets for classic and current synthetic drugsare summarised in Figure 1.
3. Overview of current synthetic drugs in thetreatment of T2DM
3.1 BiguanidesThe class of biguanides includes the metformin and two with-drawn agents phenformin and buformin. The reason forremoving phenformin and buformin from the market wasthe occurrence of fatal lactic acidosis [80,81]. Introduced inthe market in 1950, metformin is a well-accepted first-line
Insulinresistance
Thiazolidinedionesbiguanides
Biguanides
Sulphonylureasnon-
sulphonylureasGLP-1 analogsDPP4 inhibitors
Sulphonylureas
β celldysfunction
(decreased insulinsecretion)
Decreased glucose
transport (muscleand adipose tissue)
Increased hepatic glucose
production
Impairedglucose
tolerance
Obesity & lifestyle Genes
Type 2diabetemellitus
Figure 1. Pathobiology and targets for current drugs in T2DM.
Importance of synthetic drugs for T2DM drug discovery
Expert Opin. Drug Discov. (2013) 8(11) 1341
Exp
ert O
pin.
Dru
g D
isco
v. D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Se
rial
s U
nit -
Lib
rary
on
11/0
4/13
For
pers
onal
use
onl
y.
choice for the treatment of T2DM due to its good efficacy,low price and low rate of adverse effects especially in long-termuse [82-85]. Metformin reduces fasting plasma glucose concentra-tions by reducing rates of hepatic glucose production througha reduction in gluconeogenesis and glycogenolysis [86-88].Metformin also affects peripherally and improves skeletal myo-cyte glucose uptake, reduces the overall plasma free fatty acid(FFA) concentration and induces mild weight loss throughreduction of caloric intake [89,90].Activation of adenosine monophosphate-activated protein
kinase (AMPK) is required for metformin’s inhibitory effectson glucose production by hepatocytes and acetyl-CoA carbox-ylase activity and its inducing effects on glucose uptake byskeletal muscles and fatty acid oxidation. It should be noticedthat AMPK is a major cellular regulator of lipid and glucosemetabolism [91,92]. Metformin, by improving insulin sensitiv-ity, also improves a variety of other factors related to increasedcardiovascular risk. It reduces the rate of myocardial infarc-tion and all-cause mortality [93]. However, gastrointestinalintolerance, such as nausea, abdominal pain and diarrhoea,happens as a side effect in about 30% of the users that limitsthe compliance of patients to consume top effectivedoses [94,95]. Although rare, fatal lactic acidosis might beobserved in some users [96,97] and thus it should not be usedin patients with liver disease [95], renal dysfunction [97] andin those with a slight degree of creatinine elevation [98]. Thestructure of biguanide (red highlight in metformin structurein Table 1) is conventionally represented in a wrong tauto-meric form which was corrected in 2005 [99]. They are moder-ately strong bases and form HCl salts quite readily. This aspectis being exploited in the preparation of oral formulations ofmetformin with desired properties [99,100].
3.2 SulphonylureasSulphonylureas as the fast insulin secretagogues are the oldestavailable class of oral glucose-lowering agents which wereintroduced in the market in the 1940s and approved for usein 1994 for T2DM before metformin [85,95,101].These drugs specially stimulate insulin secretion in a
glucose-independent manner by binding to a regulatory pro-tein called sulphonylureas receptor on the pancreatic b-cells.After binding to the receptors, they trigger closure to KATP
channels, membrane depolarisation and influx of calciumthrough voltage-dependent channels, which subsequentlyends up in insulin secretion [102-104]. In addition to theirpancreatic effects, sulphonylureas can enhance insulin-stimulated peripheral glucose utilisation through triggeringinsulin action on adipose tissue glucose transport and lipogen-esis and skeletal muscle glycogen synthase [105,106].This class of oral drugs include the second-generation
agents glipizide, gliclazide, glibornuride, gliquidone, glisoxe-pide, glyclopyramide and glibenclamide as well as thefirst-generation agents acetohexamide, chlorpropamide, tol-azamide and tolbutamide [107]. The third-generation sulpho-nylurea glimepiride is as effective as second-generation
sulphonylureas and appears to have several clinical advan-tages over conventional sulphonylureas [108]. In clinical stud-ies, glimepiride provides more stable blood glucose control,lowers risk of hypoglycaemia and induces less weight gain incomparison to other sulphonylureas [108,109]. Owing to glime-piride pancreatic tissue specificity, its use may be safer inpatients with cardiovascular disease. Cardiovascular side effectsof these compounds result from their effect on KATP channelspresent in extra-pancreatic tissues of the cardiac and vascularsmooth muscle [110,111].
All sulphonylureas contain a central S-phenyl sulphony-lurea structure (red highlight in the glimepiride structure inthe Table 1) [107]. The pharmacokinetic and pharmacologicaldifferences among the available sulphonylureas are a conse-quence of substitutions at the para-position on the benzenering and the other at a nitrogen residue in the urea moiety [112].First-generation sulphonylureas (e.g., tolbutamide, acetohexa-mide, tolazamide and chlorpropamide) have relatively small,polar, hydrophilic substitutions. Second-generation sulphony-lureas have large, non-polar, lipophilic substitutions thatpenetrate cell membranes more easily, giving them greaterpotency [107,112].
3.3 N=lurea insulin secretagoguesAnti-diabetic and insulinotropic properties of the non-sulphonylurea moiety of glibenclamide, subsequently namedmeglitinide, have been discovered > 30 years ago. Repagli-nide, nateglinide and mitiglinide are proposed as non-sulphonylurea insulinotropic agents exhibiting structuralanalogy with meglitinide [113,114]. Repaglinide and nategli-nide have been approved for treatment of T2DM andhave been released into market in 1998 and 2001, respec-tively [115]. Repaglinide and nateglinide have a mechanismof action that is similar to that of sulphonylureas [104].They are short-acting insulin secretagogues with highaffinity and rapid association--dissociation kinetic activityto the KATP at the outer membrane of b-cells. This propertyof these compounds results in restoration of early phaseinsulin secretion [107,113]. The most common adverse eventsof repaglinide and nateglinide are upper respiratory tractinfection, sinusitis, constipation, arthralgia, headache andvomiting [116].
Nateglinide is D-phenylalanine derivative (phenylalanine ishighlighted as red in the Table 1) which blocks KATP channelsin the pancreatic b-cells to stimulate insulin release [117,118]. Intherapeutic concentrations, nateglinide with no sulphonylureaor benzamido moiety induces high selectivity for the pancre-atic KATP subtype over the cardiovascular subtype [119]. Nate-glinide sensitizes pancreatic b-cells to limited amount ofglucose and reduces the glucose concentration needed to stim-ulate insulin secretion [118]. In contrast to other insulin secre-tagogues, nateglinide has a low propensity to causehypoglycaemia because of its selective, early phase insulinsecretion and transient effect [120].
M. Safavi et al.
1342 Expert Opin. Drug Discov. (2013) 8(11)
Exp
ert O
pin.
Dru
g D
isco
v. D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Se
rial
s U
nit -
Lib
rary
on
11/0
4/13
For
pers
onal
use
onl
y.
Table
1.Currentanti-diabeticsyntheticdrugclasses.
Drugclass
Drugstructure
Mech
anism
ofaction
Sideeffects
Study
Biguanide
NN
NH
2
CH
3
CH
3NH
2N
H
Metform
in
Reduceshepaticglucose
production,increases
peripheralglucose
utilisation
andinsulin
sensitivity
Gastrointestinalcomplaints
andlactic
acidosis
Bharatam
etal.2005,
Lipskaetal.2011[99,236]
Sulphonylureas
SO
OH
NN H H N
N
O
O
OGlim
epiride
Stimulatesinsulin
release
from
pancreasandreduces
post-absorptive
ratesof
endogenousglucose
production
Very
rare
adverseeffects
comparedto
other
sulphonylureassideeffects
such
ashypoglycaemia
and
weightgain
Korytkowski2004,
Becicetal.2003
[107,237]
Non-sulphonylureas
O NH
H
HO
ONateglinide
Increasesinsulin
secretionin
thepancreas
Mild
gastrointestinal
complaints
andweightgain
Chachin
etal.2003,
Campbell2005
[119,120]
Thiazolidinediones
H NO
SN
H
O
O
N
Rosiglitazone
Lowers
insulin
resistance
inperipheraltissueby
activatingPPAR-g
Weightgain,fluid
retention
andheart
failure
Yki-Jarvinen2004,
Defronzo
2009
[125,128]
Disaccharidase
inhibitors
O OH
OH
OH
O
O OH
OH
O
HO
HO
O OH
HO
N H
HO
OH
HO
HO
H3C
Acarbose
Inhibitsintestinala-
glucosidase
enzymes
Gastrointestinaldisturbance
such
asflatulence,
abdominaldistension,
stomach
rumble
and
diarrhoea
Balfouretal.1993,
Clissold
andEdwards
1988
[141,238]
Importance of synthetic drugs for T2DM drug discovery
Expert Opin. Drug Discov. (2013) 8(11) 1343
Exp
ert O
pin.
Dru
g D
isco
v. D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Se
rial
s U
nit -
Lib
rary
on
11/0
4/13
For
pers
onal
use
onl
y.
Table
1.Currentanti-diabeticsyntheticdrugclasses(continued).
Drugclass
Drugstructure
Mech
anism
ofaction
Sideeffects
Study
GLP1agonists
Thr
Ser
Asp
Val
Ser
Glu
Gly
Gln
Ala
Ala
Lys
CO
OH
O
NH
H
O
CH
3
Glu
Phe
Ile
Ala
Trp
Leu
Val
Arg
Gly
Arg
Gly
Ser
Leu
Tyr
Phe
Thr
Gly
Glu
Ala
His
Liraglutide
Stimulatesinsulin
biosynthesisandsecretion,
inhibitsglucagonsecretion
andslowsgastricemptying
Nauseaandvomiting
Wajcberg
andAmarah
2010,Madsbad
2009
[159,239]
DPP-4
inhibitors
HN
O
N
OH
N
Vildagliptin
InhibitsDPP-4
thatim
proves
glycaemic
control
Few
gastrointestinal
disturbance
Gupta
etal.2009,
Panina2007
[168,240]
SGL2
inhibitors
OO
H
OH
OH
HO
CH
3
SF
Invokana(canagliflozin)
InhibitsSGLT2in
thekidneys
Low
incidence
of
hypoglycaemia
andgenital
infectionsin
females
Nomura
etal.2010,
Rosenstock
etal.
2012
[179,241]
Dopamine-2
agonists
HN
N
Br
HH NO
N
O O
N
HO
O
HC
H3S
O3H
Bromocriptine
Resets
abnorm
ally
elevated
hypothalamicdrive
for
increasedplasm
aglucose,
triglycerideandFFA
levels
Fatigue,nausea,vomiting,
dizziness
andheadache
Keche2010,
Kumaretal.
2012
[181,182]
M. Safavi et al.
1344 Expert Opin. Drug Discov. (2013) 8(11)
Exp
ert O
pin.
Dru
g D
isco
v. D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Se
rial
s U
nit -
Lib
rary
on
11/0
4/13
For
pers
onal
use
onl
y.
3.4 ThiazolidinedionesTroglitazone was the first thiazolidinedione approved as aglucose-lowering therapy for patients with T2DM in1997 [98,121]. Troglitazone was subsequently withdrawn fromuse, in March 2000, because of causing severe hepatic toxic-ity [122]. Two currently available PPAR-g agonists, rosiglita-zone and pioglitazone, were approved in 1999. This class ofagents also known as glitazones like the biguanide metformindo not increase insulin secretion but rather increase insulinsensitivity in muscle and adipose tissue and in the liver byactivating PPAR-g and affecting gene regulation in the targetcells [123-125].
PPAR-g is essential for normal metabolism of lipids such asadipocyte differentiation and proliferation as well as fatty aciduptake and storage [126,127]. Thiazolidinediones exert theirinsulin-sensitising actions by promoting genesis of small adipo-cytes and redirect fat from non-adipose tissues, such as liver fat,to (subcutaneous) adipose depots [125,128]. Although thiazolidi-nediones may enhance insulin sensitivity by keeping fat whereit belongs and sparing other tissues such as the liver, skeletalmuscle and possibly b-cells from lipotoxicity, indirect effectsmay also be involved via alteration of gene transcription suchas adiponectin. Adiponectin, an adipocytokine, producedexclusively by adipose tissue increases insulin sensitivity [129-131].
The potential of thiazolidinediones to lower glucose pro-duction by the liver or improve glucose transport into muscleand adipose tissue have been shown [14,132]. The main adverseevents associated with the thiazolidinediones class are weightgain and fluid retention that may be severe enough to exacer-bate or precipitate heart failure [133,134]. These drugs also causeslight decrease in the haemoglobin level and haematocrit,probably without clinical consequence [125]. Pioglitazone androsiglitazone are licensed for use as the second-line therapyto metformin and glyburide, agents that have demonstratedefficacy in decreasing the microvascular and macrovascularcomplications associated with T2DM [14].
Thiazolidine-2,4-dione structure (red highlight in the rosi-glitazone structure in the Table 1) is common to all thiazolidi-nediones [135]. Thiazolidinedione ring has been investigated aspotent polar head group which is a critical binding motif inthe active site of PPAR ligand-binding domain. However,these polar head groups are prone to racemisation underphysiological conditions [136].
3.5 Disaccharidase inhibitors (a-glucosidase
inhibitors)The a-glucosidase inhibitors acarbose and miglitol are two ofthese agents which were released in the market in 1996 [95].Initial investigations of voglibose as another disaccharidaseinhibitor have not been proceeded further [137,138]. Absorptionof carbohydrates requires eventual breakdown of disaccharidesinto monosaccharides by the a-glucosidase enzyme in the brushborder of the small intestine. Disaccharidase inhibitors, such asacarbose and miglitol, inhibit digestion of carbohydrates by
affecting the breakdown of disaccharides to monosaccharidesin the intestinal epithelium. As a consequence, delayed anddecreased absorption of the sugars happen. The a-glucosidaseinhibitors decrease both postprandial blood glucose and post-prandial insulin levels and in that way these improve sensitivityto insulin and release the stress on b-cells [139].
The safety of a-glucosidase inhibitors may be a definitehelp in elderly patients with T2DM [140]. The efficacy of acar-bose and miglitol is limited by the adverse reactions caused bya large amount of non-absorbed disaccharides in the intestinaltract with the attendant symptoms of abdominal bloating,diarrhoea and flatulence. These compounds do not inducehypoglycaemia or weight gain [139,141].
According to some studies, acarbose does not directly alterinsulin resistance but may lower postprandial plasma insulinlevels, fasting blood glucose, glycosylated haemoglobin,plasma triglycerides and/or cholesterol concentrations [141,142].Acarbose is only minimally absorbed from the gut and therebyconsidered as a non-absorbable inhibitor that makes this drugwith no systemic adverse effects even after long-term adminis-tration. The symptoms, which is due to undigested carbohy-drates, occur in ~ 30 -- 60% of patients and tend to decreasewith time and seem to be dose-dependent [142,143]. Acarbose iscomposed of an acarviosin moiety with a maltose at the reduc-ing terminus. Acarviosin is a sugar composed of cyclohexitolunit linked to a 4-amino-4,6-dideoxy-D-glucopyranose unit,which is part of the acarbose and its derivatives (highlightedas red in the Table 1) [144].
3.6 Glucagon-like peptide 1 agonistsIn April 2005, the first glucagon-like peptide 1 (GLP-1)agonist, exenatide, was approved for the treatment ofT2DM [145]. In 2010, other analogue liraglutide was approvedfor use as an adjunct to diet and exercise to improve glycaemiccontrol in adults with T2DM [146]. Several additionalGLP-1 agonists, including exenatide long-acting release [15,147]
albiglutide and taspoglutide, are under development and invarious stages of clinical trials [148].
GLP-1 is a gut-derived incretin hormone, which is secretedby the more distally located intestinal L cells. Incretin hor-mones are a group of gastrointestinal hormones released inresponse to nutrient ingestion, which cause an increase inthe amount of insulin released even before elevation of bloodglucose [149]. Incretin hormone, GLP-1 stimulates insulin bio-synthesis and secretion in response to meal ingestion, inhibitsglucagon secretion, slows gastric emptying, reduces appetiteand promotes the regeneration and proliferation of pancreaticb-cells [149-151].
Since GLP-1, gastric inhibitory polypeptide (GIP) and glu-cagon are all pivotal in glucose homeostasis, the G-protein-coupled receptors represent important drug targets in T2DM.One novel diabetes treatment strategy is activation of GLP-1receptors and inhibition of the glucagon signal [152]. The struc-ture of the human glucagon class B G-protein-coupled receptorhas been reported more recently. The distinct structural
Importance of synthetic drugs for T2DM drug discovery
Expert Opin. Drug Discov. (2013) 8(11) 1345
Exp
ert O
pin.
Dru
g D
isco
v. D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Se
rial
s U
nit -
Lib
rary
on
11/0
4/13
For
pers
onal
use
onl
y.
features and larger binding pocket of this receptor provide newinsights into the molecular details of peptide ligand bindingand a more reliable structural template for the design of specificand potent small molecules for the treatment of T2DM [153].The short half-life (t1/2 ~ 1 -- 1.5 min) of GLP-1, because
of their rapid inactivation by dipeptidyl peptidase IV(DPP-4) in the circulation, is a major difficulty for itsuse [149,154]. Exenatide is a synthetic form of exendin-4 thatoccurs naturally in the saliva of the Gila monster (a large ven-omous lizard native to southwestern United States) and itsamino acid sequence shows 53% homology to humanGLP-1 [155]. Exendin-4 and GLP-1 exhibit similar insulino-tropic potencies in both in vitro and in vivo models, whileexendin-4 has a better efficacy and a longer duration of actionthan the native GLP-1 in rodents and humans [156]. Exenatideand liraglutide exhibit increased resistance to DPP-4 degrada-tion and thus provide pharmacological levels of GLP-1. Exe-natide as short-acting GLP-1 receptor agonists (t1/2 ~ 2.4 h)is recommended for twice daily dosing [154]. Nausea, vomitingand hypoglycaemia were the most frequently reported sideeffects and were indifferent to dose while headache and naso-pharyngitis were seen more at lower dose [147]. Liraglutide, butnot short-acting exenatide, was associated with thyroidC-cell hyperplasia and tumours in rodents, probably due tocontinuous high-dose GLP-1 agonist exposure [157]. Rare casesof acute pancreatitis in association with use of incretin-based classes have been reported but the most of ensuingreports showed inconsistent results [85,158]. Liraglutide is along-acting GLP-1 analogue (t1/2 ~ 24 h), with 96% struc-tural identity to human GLP-1. The addition of a C16 fattyacid side chain using a -glutamic acid spacer at the -aminogroup of lysine-26 (fatty acid palmitate is highlighted as redin the Table 1), which allows non-covalent binding to albu-min, increases the stability through formation of heptamermediated by the fatty acid side chain [159].
3.7 DPP-4 inhibitorsDPP-4 inhibitors are promising new class of anti-diabeticsthat are extremely studied [10]. In October 2006, the firstDPP-4 inhibitor, sitagliptin, was introduced in the market.Indeed, several other drugs such as vildagliptin, saxagliptin,alogliptin, linagliptin and anagliptin have been approved incertain countries for the treatment of T2DM. Other candi-dates have been demonstrated to be in an advanced stage ofclinical trials for T2DM [160-163].Inhibition of DPP-4, a serine protease, enhances endoge-
nous GLP-1 activity by decreasing the rate of GLP-1 degrada-tion, which represents a promising approach to the treatmentof T2DM [164]. DPP-4 inhibitors increase circulatingGLP-1 and GIP levels in humans, which leads to increasedglucose-dependent secretion of insulin and decreased bloodglucose, haemoglobin A1C and glucagon levels [165,166].DPP-4 is a 766 residue N-terminal dipeptidyl exopeptidasethat specifically cleaves an amino acid sequence having prolineor alanine at the N-terminal penultimate (P1) position but
may also cleave substrate with non-preferred amino acids atthis position [167].
DPP-4 inhibitors include diverse structural types. ManyDPP-4 inhibitors have five-membered heterocyclic ringssuch as pyrrolidine, cyanopyrrolidine, thiazolidine and cyano-thiazolidine as a proline mimetic in the P1 part. Vildagliptinstructure as a cyanopyrrolidine derivatives are presented inthe Table 1 (cyanopyrrolidine ring is highlighted in red) [18].Despite the positive results of vildagliptin in clinical trials,one of the issues encountered with the use of 2-cyano pyrroli-dine derivatives is their stability in solution due to the partic-ipation of cyano group in an intramolecular cyclisationprocess leading to inactive products [168].
However, at this time, the tolerance and safety profile ofDPP-4 inhibitors are considered as excellent. Possibleincreased risk of acute pancreatitis in the short term andoccurrence of chronic pancreatitis in the longer term areamong concerns attributed to increase in GLP-1 levels.Non-consistent results regarding a possible effect of GLP-1and DPP-4 inhibitors on the exocrine pancreas were reportedin various animal models [169]. In view of likely toxic sideeffects associated with the inhibition of other members ofDPP family (inhibition of which was linked to toxicity in ani-mal studies), it seems necessary to design selective inhibitorstargeting DPP-4 over DPP-8 and DPP-9 [170]. Achievingdesired selectivity toward the inhibition of DPP-4 over otherrelated peptidases such as DPP-8 and DPP-9 and long-acting potential for maximal efficacy are the main challenges.
3.8 Sodium-glucose transporter-2 inhibitorsCanagliflozin from the new class of medications calledsodium-glucose transporter-2 (SGLT2) inhibitors wasapproved by FDA in March 2013 [171]. Although there areseveral candidates, SGLT2 inhibitors such as dapagliflozinand BI10773 are now in various stages of clinical develop-ment, and the phlorizine, sergliflozin and remogliflozin havebeen discarded [172].
Kidney plays a key role in glucose homeostasis, primarilyby the reabsorption of filtered glucose especially by theSGLT2 located in the proximal convoluted tubule. SGLT1,the other SGLTs isoform, is the key transporter for glucoseabsorption in the gastrointestinal tract and plays only a minorrole in the kidney [173,174]. The expression of SGLT2 andother renal glucose transporters were elevated in diabeticpatients [175]. SGLT2 inhibitors, with a greater selectivity forSGLT2 versus SGLT1, offer a considerable advantage aspotential anti-diabetic medications, because of their abilityto inhibit renal glucose reabsorption and subsequent plasmaglucose-lowering effect without inducing excessive insulinsecretion [172,176].
Canagliflozin, an oral selective SGLT2 inhibitor improvesglycaemic control in T2DM by reducing renal thresholdfor glucose reabsorption and increasing the urinary glucoseexcretion ending up in weight loss [177]. Various SGLT2inhibitors have been proposed based on the glucoside
M. Safavi et al.
1346 Expert Opin. Drug Discov. (2013) 8(11)
Exp
ert O
pin.
Dru
g D
isco
v. D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Se
rial
s U
nit -
Lib
rary
on
11/0
4/13
For
pers
onal
use
onl
y.
structure (glucoside ring is highlighted in red in canagliflozinstructure in the Table 1). Since, the O-linkage of the structureof SGLT2 inhibitors is a metabolic target for b-glucosidaseenzymes that can restrict the activity of SGLT2 inhibitorsin vivo, newer candidate with a C-glucoside linkage such ascanagliflozin have been synthesized [178]. Canagliflozin as aC-glucoside bearing a heteroaromatic ring has improvedmetabolic stability in comparison to O-glucoside [179].
3.9 Bile acid sequestrants/dopamine-2 agonistsFrom this category, two classes of drugs were alreadyapproved for other diseases. Colesevelam hydrochloride is abile acid sequestrant that had been originally approved forthe treatment of hypercholesterolaemia in the 2000s andapproved in January 2008 to improve glycaemic control inT2DM adults. The exact mechanism influencing glucosemetabolism remains unexplained [180].
The bromocriptine mesylate, a quick release formulationby trade name Cycloset, as an adjunct to diet and exercisehas been approved to improve glycaemic control in adultswith T2DM on 2009 [181]. Bromocriptine mesylate is a sym-patholytic D2 dopamine agonist which can reverse many ofthe metabolic alterations associated with insulin resistanceand obesity via resetting dopaminergic and sympathetic tonewithin the central nervous system [182].
Clinically, bromocriptine is used in treating Parkinson’sdisease through activity at dopamine receptors and in treatinghyperprolactinaemia and acromegaly. Bromocriptine wasused for 30 years for other indications and based on its activityin modulating central glucose and energy metabolism path-ways has been approved for the treatment of T2DM [181,183].Bromocriptine is a semisynthetic derivative that is derivedfrom a natural ergot alkaloid but bromocriptine mesylatehas been chemically designated as 2-bromoergocryptinemonomethanesulfonate (salt) [182]. More information ispresented in the Table 1.
4. New synthetic compounds asDPP-4 inhibitors
The DPP-4 is responsible for the degradation of the incretinhormones GLP-1 and GIP and has therefore a strong influ-ence on insulin secretion and glucose homeostasis [184]. Incontrast to therapy with GLP-1 analogues, because of limita-tions due to its swift inactivation, DPP-4 inhibitors increaseeffective incretin levels into a more physiological range [185].So, in the recent years, DPP-4 inhibitors have been noted asvaluable agents for treatment of T2DM. Lack of selectivitytoward several closely related proline-specific enzymes seemsa possible cause of toxicity [186]. In this review, the discoveryof some synthetic compounds which may be useful inapproach to new DPP-4 inhibitors as a new anti-diabetic classare presented. Structurally, two distinctive classes of DPP-4inhibitors have been reported [168]. Peptidomimetic inhibitorsinclude sitagliptin, vildagliptin and saxagliptin (Figure 2) and
the non-peptidomimetic inhibitors include alogliptin andlinagliptin (Figure 3).
4.1 Peptidomimetic inhibitorsThe b-methylphenylalanine-derived amides have been shownto be potent DPP-4 inhibitors, exhibiting suboptimal selectiv-ity and pharmacokinetics [187,188]. A series of phenylalanineand cyclohexylalanine derivatives also known as fluorinatedpyrrolidine amides [10] were designed and assayed for theirinhibitory potency against the DPP-4 enzyme as well as theirselectivity over the related proline-specific enzymes quiescentcell proline dipeptidase (QPP) (DPP-II), DPP-8 and DPP-9.The phenylalanine series afforded compounds such as com-pound (1) that were potent and selective. Among cyclohexyla-lanine derivatives, the acetamide b-methyl substitute (2) wasthe most potent with better oral bioavailability [189].
The effect of substitution on the imidazopiperidine-based b-amino acid derivatives inhibitory activity againstDPP-4, DPP-8 and DPP-9 was evaluated in another study.Introduction of a substituent at the 4-position of the imidazo-piperidine unit (3) produces compounds having DPP-4 IC50
values < 10 nM [190].A series of novel azobicyclo[3.3.0] octane derivatives substi-
tuted with pyrrolidine-2-carbonitrile were synthesized and eval-uated against DPP-4, DPP-8 and DPP-9. Among them,compound (4) exhibited good DPP-4 activity, high selectivity,moderate pharmacokinetic profiles and excellent in vivo effi-cacy in an oral glucose tolerance test (oGTT) in lean mice [191].
Anagliptin is a potent and highly selective DPP-4 inhibitorwhich has been approved in Japan for the treatment ofT2DM in 2012 [162,192]. A series of pyrazolo[1,5-a]pyrimidineswere found to be novel DPP-4 inhibitors. Compounds wereevaluated in vitro for inhibition of human recombinant DPP-4and also screened for selectivity over dipeptidyl peptidase8 and 9. Structure--activity relationships (SARs) for compoundsshowed N-[2-(amino)-2-methylpropyl]-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxamide hydrochloride (5) (anagliptinhydrochloride salt) as a potent and selective DPP-4 inhibitorwith unique pharmacological profile [193].
It is noteworthy that many known DPP-4 inhibitors havethe P-1--P-2 fragment, where the P-1 site contains a prolinemimic [10,194]. Pyrrolidine derivatives (vildagliptin and saxa-gliptin) have been widely explored as DPP-4 inhibitors dueto DPP-4’s specificity for substrate having an amino-terminal proline at C-2 [10]. Their cyanopyrrolidine moietiesbind to the S1 sub-site and form a covalent bond betweenthe nitrile group and hydroxyl of Ser630 in the catalytic triad.Further, their hydroxy adamantyl groups bind to the S2 sub-site [195]. Vildagliptin was chemically unstable due to intramo-lecular cyclisation between the nitrile group and the P-2 basicamine moiety. Saxagliptin has an improved chemical stabilityby introduction of a cyclopropyl ring (cis-4,5-methanobridge)to the prolinenitrile which minimises cyclisation [160,196]. TheDPP-4 inhibitors possessing the electrophilic trap such as anitrile group have low selectivity against other related prolyl
Importance of synthetic drugs for T2DM drug discovery
Expert Opin. Drug Discov. (2013) 8(11) 1347
Exp
ert O
pin.
Dru
g D
isco
v. D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Se
rial
s U
nit -
Lib
rary
on
11/0
4/13
For
pers
onal
use
onl
y.
NH2
N
O
HO
C
Saxagliptin [244,245]DPP-4 IC50: 26 nMDPP8/DPP4 > 400 foldDPP9/DPP4 > 75 fold
N
F
F
F
NH2 O
NN
N
CF3
Sitagliptin [243]DPP-4 IC50: 18 nMQPP IC50 > 100 μM DPP8 IC50: 48 μM
HN
O
N
OH
CN
Vildagliptin [246] DPP-4 IC50: 3.5 nMQPP IC50 > 500 μM
N
C
NH3+
TFA-N
CH3
O
CH3F
ONO
CH3 CH3
1 [189]DPP-4 IC50: 0.025 μMQPP IC50 > 100 μMDPP-9 IC50 > 100 μMDPP-8 IC50 > 100 μM
NH3C
CH3
O N
CH3
NH3+
Cl-
O
F
2 [189]DPP-4 IC50: 0.016 μMDPP-8 IC50: 25 μMDPP-9 IC50 > 100 μM
F
F
F
N
NH2 O
N
NCF3
CH3
H
F
3 [190]DPP-4 IC50: 0.0058 μMQPP IC50: 15 μM DPP-8 IC50: 46 μMDPP-9 IC50 > 100 μM
NCN
OHN
N
H
H
O
N
CH3
CH3
4 [191]DPP-4 IC50: 0.009 μMDPP-8 IC50: 17.38 μMDPP-9 IC50: 5.7 μM
N
CNHN
NH
O
CH3 CH3
O
N
N
N
CH3
HCl
5 [193]DPP-4 IC50: 3.8 nMDPP-8 IC50: 68 nMDPP-9 IC50: 60 nM
N
N
NH O
N
S
N
CF3
6 [194]DPP-4 IC50: 0.37 nMDPP-8 IC50: 72.4 nMDPP-9 IC50: 105 nM
N
S
O
NH
N
N
N
N
CH3
7 [197]DPP-4 IC50: 0.37 nMDPP-8 IC50: 260 nMDPP-9 IC50: 540 nM
FF
F NH
NH2 O
N
NN
N
CF3
8 [163]DPP-4 IC50: 0.031 μMDPP-8 IC50: 78.5 μMDPP-9 IC50: 41.6 μM
Figure 2. Schematic representation of chemical structure of some examples of the peptidomimetic DPP-4.
M. Safavi et al.
1348 Expert Opin. Drug Discov. (2013) 8(11)
Exp
ert O
pin.
Dru
g D
isco
v. D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Se
rial
s U
nit -
Lib
rary
on
11/0
4/13
For
pers
onal
use
onl
y.
peptidases, DPP-8 and DPP-9 [197]. The key interactions ofthe vildagliptin and saxagliptin structures with DPP-4 activesite residues are presented in Table 2.
Yoshida et al. designed novel pyrrolidine derivatives with-out electrophilic nitrile moiety focused on the substituent atthe g-position of proline moiety of prolylthiazolidine corestructure towards increasing the affinity to the S2 sub-site ofDPP-4 [194,198,199]. According to previous reports, introducingan electron-deficient 4-arylpiperazine results in highly potent
and long-lasting inhibitors [200]. Fused bicyclic heteroarylpi-perazine substituted at the g-position of the proline structurein the investigation of L-prolylthiazolidines lacking the elec-trophilic nitrile was previously explored. Compound (6)(2-trifluoroquinolyl) was the most potent, long-lasting andselective DPP-4 inhibitor. X-ray crystal structure determina-tion of compound (6) indicates that compound (6) mademany interactions with the active site of DPP-4 (Table 2).The SAR study of fused bicyclic heteroarylpiperazine parts
N
NH2
NN
O
O
CH3
CN
Alogliptin [246] DPP-4 IC50 < 10 nMDPP-8 IC50 > 100 μMDPP-9 IC50 > 100 μM
N
NN
N
O
O
CH3
N
NN
NH2CH3
Linagliptin [247] DPP-4 IC50: 1 nMQPP IC50 > 100 μMDPP-8 IC50: 40 μMDPP-9 IC50 > 10 μM
F
F
F N
NH3+TFA-
NN
N O
9 [201] DPP-4 IC50: 1.2 nMQPP IC50: > 100 μMDPP-8 IC50 > 100 μMDPP-9 IC50 > 19 μM
N
N N
N
O
H
N
NH2
NN
10 [203]DPP-4 IC50: 0.001 μMDPP-4 inhib. in rat: 80%Muscarinicreceptor M1 IC50: 1.190 μM
N
NN
NH2
Cl
Cl
11 [204] DPP-4 Ki: 0.006 μmDPP-8 Ki: > 30 μMDPP-9 Ki: > 30 μM
NH2
H
N
F
F
O
N
CH3
CH3CH3
O2S
12 [206]DPP-4 IC50: 0.055 μM QPP IC50: 63 μMDPP-8 IC50 > 100 μMDPP-9 IC50 > 100 μM
F
F NH
NH2
N
CO2NH2
13 [206]DPP-4 IC50: 0.018 μMQPP IC50: 22 μMDPP-8 IC50: 18 μMDPP-9 IC50: 27 μM
CH3
N
NNH2
H3C CH3
HNO
O
14 [207] DPP-4 IC50: 1.3 nMQPPIC50: 20 μMDPP-8 IC50 > 60 μMDPP-9 IC50 > 60 μM
N
O
N
N
N
NH2C
Cl
F
O
OH
CH3
15 [208] DPP-4 IC50: 0.48 nMQPP IC50 > 10 μMDPP-8 IC50 > 100 μMDPP-9 IC50 > 100 μM
Figure 3. Schematic representation of chemical structure of some examples of the non-peptidomimetic DPP-4 inhibitors.
Importance of synthetic drugs for T2DM drug discovery
Expert Opin. Drug Discov. (2013) 8(11) 1349
Exp
ert O
pin.
Dru
g D
isco
v. D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Se
rial
s U
nit -
Lib
rary
on
11/0
4/13
For
pers
onal
use
onl
y.
Table 2. Key interactions between inhibitor structures and DPP-4 active site residues.
DPP-4 inhibitor Involved inhibitor structure Interaction type DPP-4 residue Study
Linagliptin Amino group on the piperidine Hydrogen bonding interactions Glu205, Glu206and Tyr662
Eckhardt et al.2007 [202]
C-6 carbonyl of the xanthine Hydrogen bonding interactions Tyr631Quinazoline group Stacking interactions Trp629Uracil group Stacking interactions Tyr547
Saxagliptin Amino group (primary) Hydrogen bonding interactions Glu205, Glu206and Tyr662
Metzler et al.2008 [242]
Carbonyl group Hydrogen bonding interactions Asn710Hydroxyl group on theadamantyl moiety
Hydrogen bonding interactions Tyr 547
Imidate nitrogen Hydrogen bonding interactions Tyr 5474,5-Methanopyrrolidine ring van der Waals interactions Val711, Val656, Tyr662,
Tyr666, Trp659and Tyr547
Nitrile of the cyanopyrrolidine Covalent bond Ser630Sitagliptin b-Amino group Hydrogen bonding interactions Glu205, Glu206
and Tyr662Zhu et al. 2013,Kim et al.2005 [163,243]Carbonyl group Hydrogen bonding interactions Tyr547
Triazolopiperazine Stacking interactions Phe357Trifluoromethyl group onthe triazolopiperazine
Ionic Bonds Arg358 and Ser209
Trifluorobenzyl group Hydrophobic interactions Ser630, His740, Trp659,Tyr631, Tyr662and Tyr666
Vildagliptin Amino group Salt bridge interactions Glu205, Glu206 Nabeno et al.2013 [195]Carbonyl group Hydrogen bonding interactions Asn710
Hydroxyl group on theadamantyl moiety
Hydrogen bonding interactions His126 and Ser209
Imidate nitrogen Hydrogen bonding interactions Tyr547Nitrile of the cyanopyrrolidine Covalent bond Ser630
6 Amino group of the proline Salt bridge interactions Glu205 and Glu206 Yoshida et al.2012 [194]Carbonyl group Hydrogen bonding interactions Asn710
Quinolyl ring Stacking interactions Phe357CH--p interaction Arg358
Trifluoromethyl on thequinolyl ring
Imperfect interaction Tyr585
7 (teneligliptin) Amino group of the proline Salt bridge interactions Glu205 and Glu206 Yoshida et al.2012 [197]Carbonyl group Hydrogen bonding interactions Asn710
Phenyl on the pyrazolyl ring Hydrogen bonding interactions Ser209 and Arg358Hydrogen bonding interactions Val207
Piperazinyl ring CH--p interaction Phe357Pyrazolyl ring Hydrophobic interactions Phe357
8 Amino group Salt bridge interactions Glu205 and Glu206 Zhu et al.2013 [163]Trifluoromethyl group on
the triazolopiperazine-Interactions Tyr585 and Arg356
14 Amino group on thequinoline ring
Hydrogen bonding interactions Glu205, Glu206and Tyr662
Maezaki et al.2011 [207]
2-Isobutyl group Hydrophobic interaction Phe3572-Oxo group on thepiperazin-2,5-dione
Hydrogen bonding interactions Lys554
5-Oxo group on thepiperazin-2,5-dione
Hydrogen bonding interactions Tyr631
Piperazin-2,5-dione ring Hydrophobic interaction Tyr54715 Amino group at the piperidine
moiety (primary)Salt bridge interactions Glu205 and Glu206 Ikuma et al.
2012 [208]
Carbonyl group on thequinoline ring
Hydrogen bonding interactions Tyr631
Carboxyl group on thebenzene ring
Salt bridge interaction Lys554
3H-imidazo[4,5-c]quinolin-4(5H)-one moiety
Stacking interactions Tyr547
M. Safavi et al.
1350 Expert Opin. Drug Discov. (2013) 8(11)
Exp
ert O
pin.
Dru
g D
isco
v. D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Se
rial
s U
nit -
Lib
rary
on
11/0
4/13
For
pers
onal
use
onl
y.
of previous study revealed that the non-linear (L-shaped)structure was more suitable than the linear (I-shaped) one inDPP-4 inhibitory activity. Moreover, the X-ray crystal struc-ture determination of compound (6) in complex with humanDPP-4 indicated that interaction between the quinolyl ringand the S2 extensive sub-site plays an important role forDPP-4 inhibition [194]. Hence, the introduction of anothernon-linear structure, a linked bicyclic heteroaryl group onthe piperazine or piperidine moiety, instead of a fused bicyclicheteroaryl group, was addressed in the latter study which ledto discovery of 3-[(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyra-zol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl]thiazolidine(7), as highly potent, selective, long-lasting and orally activeDPP-4 inhibitor. The X-ray co-crystal structure of compound(7) in DPP-4 demonstrated that the characteristic five rings ofcompound (7) fit into the active site of DPP-4 and the keyinteraction between the phenyl substituent on the pyrazolylring and the S2 extensive sub-site of DPP-4 not only raisedpotency, but also increased selectivity (Table 2). Compound(7) significantly inhibited the increase of plasma glucose levelsafter an oral glucose load in Zucker fatty rats. Compound (7)(teneligliptin) has been approved for the treatment of T2DMin Japan on June 2012 [197].
The crystal structures of DPP-4 in complex with boundsitagliptin and alogliptin have shown that a sub-pocketformed by the catalytic residue Ser630 and nearby residuesis usually occupied by a hydrophobic ring group such as thetrifluorobenzyl group of sitagliptin or the benzonitrile of alog-liptin. Two acidic residues -- Glu205 and Glu206 -- in the S2sub-site of DPP-4 forms interactions with amine group ofsitagliptin (Table 2). These interactions between sitagliptinand DPP-4 give a large unoccupied space around the right ter-minal portion (the fused heterocyclic ring) which could bemodified to generate a new series of DPP-4 inhibitors. Withthis rationale, well-established click chemistry was used toquickly explore the SAR of the linker and the terminal por-tion of sitagliptin. A series of 4-(2,4,5-trifluorophenyl)butane-1,3-diamines were designed and elaborated as DPP-4inhibitors. The results showed that compound (8) had desir-able efficacy, selectivity and pharmacokinetics properties. Itis noteworthy that crystal structures of DPP-4 in complexwith bound compound (8) revealed that the trifluoromethylheterocycle is rotated ~ 180� and directed towards a sub-pocket different from the sub-site bound by sitagliptin, pro-viding clues for the design of new DPP-4 inhibitors. Thekey interaction between compound (8) and DPP-4 activesite are presented in Table 2 [163].
4.2 Non-peptidomimetic inhibitorsMonocyclic, bicyclic, bicyclic lactams and triazolopyridazines-substituted 3-aminopiperidines were synthesized and evalu-ated for in vitro inhibition of human DPP-4, QPP, DPP-8and DPP-9. Bicyclic lactams series were potent (DPP-4IC50: 1.2 -- 8 nM) and in general had good-to-excellent selec-tivity. Compound (9) was found to be the most potent
DPP-4 inhibitor with excellent selectivity but poor pharmaco-kinetic properties [201].
The X-ray crystal structure of linagliptin complexed withDPP-4 indicated the manner in which these residues provideda good fit (Table 2) [202]. A class of 3,5-dihydro-imidazo[4,5-d]pyridazin-4-ones with different substituent provided.In addition to in vitro DPP-4 inhibitory activity, the effectsof compounds on the muscarinic receptor M1 and inhibitionof DPP-4 in rats was tested. It should be noticed that signifi-cant M1 receptor inhibition was a characteristic of some earlyxanthines. Compound (10) seems to be a potential candidateshowing very potent DPP-4 inhibitor activity in vitro as wellas in vivo and only poor affinity to M1 receptors. The long-lasting strong DPP-4 inhibition (> 70% 24 h post-adminis-tration) of compound (10) is particularly noteworthy. There-fore, further works on this series, and compound (10) inparticular, will be helpful in the development of better drugsfor T2DM [203].
Pyrazolopyrimidines are a class of compounds under inves-tigation. A series of pyrazolopyrimidines with different sub-stituents on the pyrazole ring which include alkyl, aryl,substituted aryl and carboxylic ester groups were testedin vitro against purified human DPP-4. FavourableDPP-4 activity, selectivity over DPP-8 and DPP-9 and ampleopportunity for further optimisation around the pyrazole ringwere the three desirable characteristics of this class of com-pounds. A 5-aminomethyl imidazolopyrimidines derivativecompound (11) was the most potent against DPP-4 with nosignificant DPP-8/DPP-9 inhibition. The oGTT in ob/obmice by compound (11) showed dose-dependent increase inplasma insulin levels [204].
While substituted 4-amino cyclohexylglycine analogues inthe a-amino acid series showed good activity againstDPP-4 [205], the substituted cyclohexane and piperidine deriv-atives were prepared and assessed for DPP-4 inhibitory activ-ity and selectivity profiles against other proline-specificpeptidases. In the cyclohexyl with sulphonamide substituentseries, N-methyl-(2,5-dimethylisoxazol-yl)sulphonamide (12)showed the most promising potency against DPP-4 andexcellent selectivity against the off-target enzymes but poorpharmacokinetic. Among the N-substitution piperidine deriv-atives, 3-(5-aminocarbonylpyridyl piperidine) (13) displayedexcellent DPP-4 activity with good selectivity versus otherproline enzymes [206].
As mentioned in Table 2, many of the reported DPP-4inhibitors including vildagliptin and saxagliptin make a cova-lent interaction with the Ser630 residue in the S1 pocket. Sita-gliptin and linagliptin form non-covalent interactions withthe S’1, S’2 or S2 extensive sub-sites in addition to theS1 and S2 sub-sites. It appears that excess interactions mayincrease DPP-4 inhibition beyond the level yielded by thefundamental interactions with the S1 and S2 sub-sites andare more effective than forming a covalent bond withSer630 in the S1 subunit [195,207]. Design of novel non-covalent inhibitors of DPP-4 using structural information
Importance of synthetic drugs for T2DM drug discovery
Expert Opin. Drug Discov. (2013) 8(11) 1351
Exp
ert O
pin.
Dru
g D
isco
v. D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Se
rial
s U
nit -
Lib
rary
on
11/0
4/13
For
pers
onal
use
onl
y.
derived from DPP-4 structures co-crystallised with small mol-ecules originating from different chemical classes is now a vitalinvestigation in medicinal chemistry.Based on the X-ray co-crystal structure of some com-
pounds, the hydrogen bonding interaction with Lys554 maybe applicable in the novel design of DPP-4 inhibitors. Hence,Maezaki et al. developed a novel series of non-covalent quin-oline-based inhibitors to target the side chain of Lys554. Syn-thesis and evaluation of designed compounds against DPP-4,QPP, DPP-8 and DPP-9 enzyme and determination ofabsorption, distribution, metabolism and excretion and phar-macokinetic profiles revealed 1-[3-(aminomethyl)-4-(4-methyl-phenyl)-2-(2-methylpropyl) quinolin-6-yl]piperazine-2,5-dionecompound (14) -- a potent, selective and orally activeDPP-4 inhibitor with long-lasting ex vivo activity in dogs andpotent glucose-lowering effects in rats. A docking study of com-pound (14) suggested that an efficient fit into the binding siteand a hydrogen-bonding interaction with the side chain ofLys554 are important in enhancing the inhibitory activity.Also, in comparison with other members of this series, it seemsthat compound (14) achieved excellent activity by taking advan-tage of the desirable piperazin-2,5-dione substituent and form-ing hydrophobic and two hydrogen-bonding interactions,including the one with Lys554 (Table 2) [207].Ikuma et al. found a potent DPP-4 inhibitor by high-
throughput screening of laboratory chemical library andproper optimisation based on results of published DPP-4enzyme-inhibitor docking study. Further docking studieswere carried out to design a strategy for optimisation of leadcompound with 3H-imidazo[4,5-c]quinolin-4(5H)-one asskeleton. Compound (15) with 2-chloro-5-fluorobenzylsub-stituent on the imidazoquinoline group was found as potentand highly selective DPP-4 inhibitor [208]. The results ofdocking study are shown in Table 2.
5. New synthetic compounds asSGLT2 inhibitors
Inhibition of glucose reabsorption and increasing urinaryglucose excretion lead to a negative energy balance, makingthese series of compounds a unique promising therapeuticclass with potential to reduce body weight in T2DM [172].Only sugars in a hexose and the D-configuration are translo-cated by SGLT. The hydrogen bonding between SGLT2 andhydroxy groups at C-2, C-3 and C-4 and hydrophobic inter-actions with the C-6 methylene group of the pyranose are thekey interactions in determining sugar specificity [209,210]. Theb-glucosides with large ring structures such as aromatic aglu-cones and the aglucones themselves are well accommodatedat the sugar-binding site and not translocated. They act asinhibitors of the transport [174,209]. Various O-, C-, N- andS-glucosides have been synthesized with high affinity andhigh specificity for SGLT2 that are in the different stages ofclinical development [209]. The b-glucoside phlorizin, the firstSGLT2 inhibitors, is a O-aryl glycoside and non-selective
competitive inhibitor with two moieties to bind with SGLT:a glucose moiety connected with an oxygen atom (O-glucoside)and a hydrophobic aglycone moiety [209,211]. The first-generation SGLT2 inhibitors with O-glycosidic bond werediscontinued due to their short half-lives in vivo resultingfrom glycosidase cleavage [211,212]. Second-generation SGLT2inhibitors adopted other forms of glycoside linkage resistantto glycosidase activity such as C-glucoside structure [213].
5.1 C-glycoside analogues of SGLT2 inhibitorsMany C-aryl glycoside analogues containing conjugated arylmoiety with glucose moiety by C--C bond instead of instableC--O--C bond have been designed and synthesized [179,214].Among these analogues, dapagliflozin has been used as alead compound as many synthetic derivatives have been fur-ther made on its SAR data. A series of fluorinated analoguesof dapagliflozins were designed and synthesized by incorpo-ration of a gem-difluoromethylene group at C-4 position.The in vitro inhibitory activities of these series against humanSGLT2 showed that some of the analogues (compound 16)with CF2 at C-4 are better SGLT2 inhibitors comparedwith dapagliflozin (Figure 4) [215].
The structural similarity of D-xylose and D-glucose and thepositive results of O-xylosides and N-b-D-xylosides [216] led tothe design of a new series of C-linked indolylxylosides. SARsstudies indicated that a p-cyclopropylphenyl group in the dis-tal position and substituents at the 7-position of the indolemoiety were necessary for optimum inhibitory activity. Thepharmacokinetic and animal studies demonstrated that themost potent compound 7-substituted indolylxlyosides bearinga distal p-cyclopropylphenyl group (17) is metabolically stablewith significant efficacy on lowering blood glucose levels ofstreptozotocin-induced diabetic rats [217].
Ikegai et al. investigation led to the discovery of otherC-glucoside SGLT2 inhibitors with azulene motifs [218].Although azulene is not a common motif in medicinal chem-istry of anti-diabetic drug discovery, a search of the literatureindicates that certain azulene derivatives possess significantpharmacological and therapeutic activity [219-221]. Hence, aseries of C-glucosides with azulene rings in the aglycone moi-ety was synthesized; SAR of azulene-derived C-glucoside andthe inhibitory activities towards hSGLT1 and hSGLT2 wereexplored. Incorporation of a phenolic hydroxyl group at thecentral benzene ring afforded a more potent and selectiveSGLT2 inhibitor (18), which exerted a strong and sustainedanti-hyperglycaemic effect in rodent diabetic models.A mono choline salt of compound (18) (YM543) was selectedas a clinical candidate for use in treating T2DM [218].
A new class of potent and selective SGLT2 inhibitors, bymodifying the glycone side chain incorporating a structurallynovel dioxabicyclo-[3.2.1]octane ring system, was pre-pared [222]. At first, a series of C-5-spirocyclic C-glycosidewere synthesized with relatively good potency and selectivityfor human SGLT2 but suboptimal pharmacokinetics [223].The medicinal chemistry strategy by innovative chemistry
M. Safavi et al.
1352 Expert Opin. Drug Discov. (2013) 8(11)
Exp
ert O
pin.
Dru
g D
isco
v. D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Se
rial
s U
nit -
Lib
rary
on
11/0
4/13
For
pers
onal
use
onl
y.
that allowed difficult, yet very desirable, targets to be synthe-sized in an analogue-friendly fashion and the development ofa pharmacokinetics/pharmacodynamics (PKPD) modelbrought more hope. These efforts led to deprioritisation ofthe C-5-spirocyclic C-glycoside SGLT2 inhibitors and focus-ing on the dioxabicyclo[3.2.1]octane class. It is believed thatthe bridged ketal system would confer rigidity with poten-tially positive impact on potency and selectivity. Moreover,introduction of a hydroxymethylene H-bond donor group at
C-5 (in place of the spirocycle) brought more anticipationto reduce the rate of human Phase II metabolism and furtherimprovement of the potency. These efforts supported theadvancement of compound (19) (PF-04971729) into clinicaldevelopment that is being evaluated for the treatment ofT2DM [222].
Vyas et al. performed a ligand-based 3D quantitative SARs(QSARs) study on C-aryl glucoside SGLT2 inhibitors(180 analogues), which belong to various diversified
O
OH
OH
HO
HO
O
HO OHOH
O
Phlorizin [215]SGLT2 IC50: 46.03 nM
O
OH
OH
HO
Cl O
HO
CH3
Dapagliflozin [214]SGLT2 EC50: 1.1 nMSGLT1/SGLT2: 1200 fold
OH
OH
HO
HO
OCH3
O
Sergliflozin-A [249]SGLT2 Ki: 2.39 nMSGLT1/SGLT2: 296 fold
O
OH
OH
HO
FF
Cl O
CH3
16 [215]SGLT2 IC50: 0.35 nM
O
OHHO
OH
N
F
17 [217] SGLT2 EC50: 47 nMSGLT1/SGLT2: 6 fold
O
OH
OH
HO
HO
HO
18 [218] SGLT2 IC50: 8.9 nMSGLT1/SGLT2: 280 fold
O
OH
OH
HO
Cl O
HO
CH3
O
19 [222] SGLT2 IC50: 0.887 nMSGLT1/SGLT2 > 2234 fold
NN
NH
HO
(CH3)3
20 [225] SGLT2 EC50: 3.85 μM
OH
OH
HO
HO
OCH3
O
21 (pseudo-sergliflozin) [227]SGLT2 IC50: 2.45 nMSGLT1/SGLT2 > 200000 fold
O
OH
OH
HO
HO
S
N N
S
22 [228]Inhibition rate of blood glucose levels in oGTT: 74.85%
O
OH
OH
HO
N
Cl
23 [216] SGLT2 EC50: 161 nMSGLT1/SGLT2: 1.3 fold
Figure 4. Schematic representation of chemical structures of some SGLT2 inhibitors together with their experimental
inhibitory and selectivity activities.
Importance of synthetic drugs for T2DM drug discovery
Expert Opin. Drug Discov. (2013) 8(11) 1353
Exp
ert O
pin.
Dru
g D
isco
v. D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Se
rial
s U
nit -
Lib
rary
on
11/0
4/13
For
pers
onal
use
onl
y.
structures such as benzisothiazole, indolizine-b-D-glucopyra-noside, thiazolylmethylphenyl, pyridazine, thiazole andpyrimidinylmethylphenyl glucoside analogues. Comparativemolecular field analysis (CoMFA) and comparative molecularsimilarity indices analysis (CoMSIA) were used to furtherexplore the structural requirements of C-aryl glucoside ana-logues for SGLT2 inhibition. CoMFA and CoMSIA contourmap analysis offered enough information to understand theimportance of the substituent at particular positions withrespect to steric, electrostatic, hydrophobic, hydrogen-bonddonor and acceptor properties for better activity of C-aryl gluco-side SGLT2 inhibitors. For example analysis of CoMFA andCoMSIA contour plots revealed the importance of hydrophobicand hydrogen-bond donor and acceptor properties [224].
5.2 SGLT2 inhibitors with other structuresThe application of ligand-based virtual screening strategycomprising the combination of pharmacophore model withshape-based scoring and structure clustering analysis led tothe discovery of non-glycoside SGLT2 inhibitors. A total of7989 compounds matching all the features described by phar-macophore model were then subjected to shape-based scoringand structure clustering analysis. Totally, 80 compounds withhigh score and structurally diverse scaffolds were selected forbiological testing, and out of these, three compounds showedinhibition of SGLT2 with EC50 < 10 µM. The non-glycosidecompound (20) with EC50 = 3.85 µM was the most potentcompound [225].Most SGLT2 inhibitors in clinical trials are taken from two
distinct series: C-aryl glycosides (e.g., dapagliflozin) andO-aryl glycosides (e.g., sergliflozin and remogliflozin) [223].The abovementioned compounds were C-glucoside deriva-tives but showed higher cancer risk [226]. It is thought thatthe metabolic instability of the O-glucoside SGLT2 inhibitorscan be solved by modifying the sugar core of sergliflozin-A.Several small-molecule carbohydrate mimics such as pseudo-sergliflozin were synthesized by a region- and stereo-selectiveallylic substitution reaction. Then the SGLT2/SGLT1 inhib-itory activities of these newly synthesized compounds werestudied. The endocyclic oxygen atom of sergliflozin-A wasreplaced by a methylene unit to render the molecule freefrom glycosidase degradation. In this way, compound (21)was found as a potent and selective inhibitor of SGLT2 thatconsidered a lead compound for further development [227].A series of thiadiazole-based S-glycosides were synthesized
from D-glucose, D-galactose and a variety of phenylacetic acidsand then evaluated in vivo with an oGTT test. Of these,5-benzyl-1,3,4-thiadiazol-2-yl 1-thio-b-D-glucopyranoside(22) was the most efficacious to suppress the blood glucoseexcursion during oGTT with the inhibition rates of bloodglucose levels equal to 74.85% [228].Since, N-linked glycosides were expected to have greater
metabolic stability compared to O-glucosides, a novel seriesof N-linked b-D-xylosides were synthesized and evaluatedfor inhibitory activity against SGLT2 in a cell-based assay.
Among them, the 4-chloroindolyl-N-xyloside with the4-cyclopropylbenzyl at the distal position (23) was found themost potent inhibitor with no selectivity for SGLT2 overSGLT1. According to pharmacokinetic data, compound(23) was metabolically stable with a low clearance and goodoral bioavailability in Sprague Dawley rats [216].
7. Conclusion
More recently, the need to develop new drugs for T2DM as amulti-causal and complicated disease has been emphasized, asthe worldwide incidence of this disease is increasing dramati-cally. Various drug options are now available for the manage-ment of T2DM, but almost all are associated with restrictionsand most do not address all aspects of the defects in diabeticpatients. The recently introduced DPP-4 and SGLT2 inhibi-tors effectively lower the blood glucose without weight gainand risk of hypoglycaemia.
The co-crystal structures of human DPP-4 with someapproved inhibitors are available. So, in recent years, new syn-thetic DPP-4 inhibitors with diverse chemical structures havebeen found, according to the X-ray crystal structure ofDPP-4 and computer-modelling studies. Remarkable creativ-ity and thoughts have been demonstrated by medicinal chem-ists in designing novel and potent series of DPP-4 inhibitors.Various SGLT2 inhibitors based on the glucoside structure ofphlorizin, sergliflozin, dapagliflozin, canagliflozin and otherinhibitors in clinical trial have since been proposed. Alternativecandidate SGLT2 inhibitors that have also been consideredinclude modified sugar rings, N-glucosides, S-glucosides, non-glycoside and, more recently, bridged ketal ring, azulenemotifs. The other promising agents targeting novel molecularmechanisms are under development. The hope is to discovermore selective and effective anti-diabetic agents in thenear future.
8. Expert opinion
Despite a rapid increase in the number of drugs available totreat hyperglycaemia, diabetes still remains a major globalconcern. Although three oldest classes comprising insulin, sul-phonylureas and the biguanides are effective in improvingoutcome, they are unable to sustain adequate glycaemiccontrol over time in the diabetic patients. A variety of anti-hyperglycaemic drugs with different and complementarymechanisms of action are currently available. Moreover, theuse of current medications is often limited by their sideeffects, mostly sudden hypoglycaemia, weight gain, gastroin-testinal effects or oedema. These factors necessitate the ongo-ing quest for novel agents that would address fundamentaldefects of T2DM and have minimal adverse effects.
Among the main anti-diabetic drug classes, DPP-4 andSGLT2 inhibitors are novel and promising therapy forT2DM. The details of synthesis backgrounds of many newDPP-4 inhibitors, in the recent years, are described in this
M. Safavi et al.
1354 Expert Opin. Drug Discov. (2013) 8(11)
Exp
ert O
pin.
Dru
g D
isco
v. D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Se
rial
s U
nit -
Lib
rary
on
11/0
4/13
For
pers
onal
use
onl
y.
review. In this review, the structures of some compounds withbiological properties are also presented. Phenylalanine andcyclohexylalanine derivatives and imidazopiperidine-basedb-amino acid derivatives were designed based on the observa-tion that modification of the phenylalanine, cyclohexylalanineor piperazine moiety improved the DPP-4 potency by severalfolds. Also the 3-fluoropyrrolidine analogues obtained byreplacing the pyrrolidine ring compounds (1) and (2) showedmore activity compared to parent compound [189,190]. Sincebicyclo[3.3.0]octane derivative with pyrrolidine-2-carbonitrilewas previously reported to be a potent DPP-4 inhibitor [191],azobicyclo[3.3.0]octane compounds were synthesized. The dis-covery of anagliptin was according to studies showed that pyr-azolo[1,5-a]pyrimidine functions as a bioisostere conveyingmuch metabolic stability and safety [193].
A costly component of drug discovery approaches isstructure-based screening (docking), which is a design strategyfor new chemical entities, or optimisation of lead compoundsidentified by other methods, using the 3D structure of theDPP-4. The 3D structure of DPP-4 could be obtained byX-ray or nuclear magnetic resonance studies or from homol-ogy models. The protein data bank is a repository for the3D structural data of proteins. The crystal structures ofDPP-4 have been previously disclosed and the discovery ofteneligliptin performed by aid of mentioned in silico methodswhich comprise computationally assessed ligand-bindinginteractions with DPP-4. Non-peptidomimetic inhibitors ofDPP-4 such as 3-aminopiperidines with bicyclic lactams sub-stituents were originated from sitagliptin -- a peptidomimeticDPP-4 inhibitor, X-ray crystallographic structure along withmolecular modelling [201]. Also non-covalent quinoline-basedinhibitors which target the side chain of Lys554 were designedbased on the X-ray co-crystal structure of some compoundscontaining hydrogen bonding interaction with Lys554 [207].Numerous DPP-4 inhibitors that were discovered and/or opti-mised using in silico methods have reached the level of clinicalstudies or have gained approval of use in some countries.
Stability and selectivity of SGLT2 inhibitors is animportant issue in drug design. The SARs studies ofphlorizin and other candidates led to discovery of anotherselective and potent SGLT2 inhibitor with excellent phar-macokinetic properties. Discovery of dioxabicyclo[3.2.1]octane was supported by analogue-friendly fashion andPKPD model [222].
The X-ray crystal structure of SGLT2 is yet not available;thus, to explore the structural requirements for SGLT2 inhi-bition, the ligand-directed drug model was used to screenactive compounds as templates. Ligand-based screening tech-niques mainly focus on comparing molecular similarity anal-yses of compounds with known and unknown moiety. The3D QSAR methods of CoMFA and CoMSIA models havebeen developed as ligand-based approaches. As mentioned,CoMFA and CoMSIA models were successfully used in pro-viding useful information for designing new SGLT2 inhibi-tors [224]. Computer-aided drug design plays an importantrole in drug discovery and development and provides usefulinsights into experimental findings and mechanism of actionand new suggestions for molecular structures to synthesize.In this way, large databases of compounds can be testedin silico with cheaper and faster techniques before submittingto in vitro expensive synthesis [229].
Most classic anti-diabetic drugs target the major pathophys-iological defects in T2DM, namely insulin resistance andimpaired insulin secretion, while the new developing drugsfocus on other options such as SGLT2 inhibitors that affectthe kidney through insulin-independent mechanisms.Recently, PPARa/ dual agonists [230], SIRT1 activators [231,232],glycogen phosphorylase inhibitors [233] and protein tyrosinephosphatase 1B inhibitors [233-235] were luckily designed forthe treatment of T2DM.
There is no doubt that T2DM and its related complica-tions are associated with oxidative stress that plays a role inthe pathogenesis of T2DM. Antioxidant (natural or synthetic)therapy can protect b-cells from apoptosis and might posi-tively work in control of hyperglycaemia by activating theproduction and release of insulin [13,66,74].
Finding new targets and new faster and cheaper synthesismethods are the main goal in T2DM drug discovery. No sin-gle diabetes treatment is best for everyone as each personresponds in a different way to medication. Together, the avail-able and rising drug candidates should provide physicianswith a broad range of pharmacological choices to successfullyindividualise patient treatment.
Declaration of interest
The authors state no conflict of interest and have received nopayment in preparation of this manuscript.
Importance of synthetic drugs for T2DM drug discovery
Expert Opin. Drug Discov. (2013) 8(11) 1355
Exp
ert O
pin.
Dru
g D
isco
v. D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Se
rial
s U
nit -
Lib
rary
on
11/0
4/13
For
pers
onal
use
onl
y.
BibliographyPapers of special note have been highlighted as
either of interest (�) or of considerable interest(��) to readers.
1. Alberti KG, Zimmet PZ. Definition,
diagnosis and classification of diabetes
mellitus and its complications. Part 1:
diagnosis and classification of diabetes
mellitus provisional report of a WHO
consultation. Diabet Med
1998;15:539-53
2. Beletate V, El Dib RP, Atallah AN. Zinc
supplementation for the prevention of
type 2 diabetes mellitus.
Cochrane Database Syst Rev
2007(1):CD005525
3. Kuzuya T, Nakagawa S, Satoh J, et al.
Report of the Committee on the
classification and diagnostic criteria of
diabetes mellitus. Diabetes Res
Clin Pract 2002;55:65-85
4. Kuzuya T, Matsuda A. Classification of
diabetes on the basis of etiologies versus
degree of insulin deficiency.
Diabetes Care 1997;20:219-20
5. American diabetes association. Diagnosis
and classification of diabetes mellitus.
Diabetes Care 2008;31(Suppl 1):S55-60
6. Sollu M, Banji D, Banji OJF,
Kumbala VCS. Appraisal on causes and
treatment of diabetes mellitus. Arch Appl
Sci Res 2010;2(5):239-60
7. McCarthy MI. Genomics,
type 2 diabetes, and obesity. N Engl
J Med 2010;363:2339-50
8. Mostafalou S, Abdollahi M. Pesticides
and human chronic diseases: evidences,
mechanisms, and perspectives.
Toxicol Appl Pharmacol
2013;268:157-77
9. Hadjibabaie M, Gholami K, Khalili H,
et al. Comparative efficacy and safety of
atorvastatin, simvastatin and lovastatin in
the management of dyslipidemic
type 2 diabetic patients. Therapy
2006;3:759-64
10. Havale SH, Pal M. Medicinal chemistry
approaches to the inhibition of
dipeptidyl peptidase-4 for the treatment
of type 2 diabetes. Bioorg Med Chem
2009;17:1783-802
. Comprehensive review which focuses
on the journey of drug discovery of
DPP-4 inhibitors for oral delivery.
11. Hosseini A, Abdollahi M. Diabetic
neuropathy and oxidative stress:
therapeutic perspectives. Oxide Med
Cell Longev 2013;2013:168039
12. McLennan SV, Abdollahi M, Twigg SM.
Connective tissue growth factor, matrix
regulation, and diabetic kidney disease.
Curr Opin Nephrol Hypertens
2013;22:85-92
13. Rahimi R, Nikfar S, Larijani B,
Abdollahi M. A review on the role of
antioxidants in the management of
diabetes and its complications.
Biomed Pharmacother 2005;59:365-73
14. Crane PK, Walker R, Hubbard RA,
et al. Glucose levels and risk of
dementia. N Engl J Med
2013;369(6):540-8
15. Bastaki S. Diabetes mellitus and its
treatment. Int J Diabetes Metab
2005;13:111-34
16. Salari P, Nikfar S, Abdollahi M. No
superiority of exenatide over insulin in
diabetic patients in terms of weight
reduction or incidence of adverse effects:
a meta-analysis. Int J Pharmacol
2011;7:749-56
17. Freeman JS. The increasing epidemiology
of diabetes and review of current
treatment algorithms. J Am
Osteopath Assoc 2010;110:eS2-6
18. Monika G, Sarbjot S, Punam G.
Dipeptidyl peptidase-4 inhibitors: a new
approach in diabetes treatment. Int J
Drug Dev Res 2009;1:146-56
19. Nathan DM, Buse JB, Davidson MB,
et al. Medical management of
hyperglycemia in type 2 diabetes:
a consensus algorithm for the initiation
and adjustment of therapy: a consensus
statement of the American Diabetes
Association and the European Association
for the Study of Diabetes. Diabetes Care
2009;32:193-203
20. Momtaz S, Abdollahi M. An update on
pharmacology of Satureja species; from
antioxidant, antimicrobial, antidiabetes
and anti-hyperlipidemic to reproductive
stimulation. Int J Pharmacol
2010;6(4):454-61
21. Abdollahi M, Zuki AB, Goh YM, et al.
Effects of Momordica charantia on
pancreatic histopathological changes
associated with streptozotocin-induced
diabetes in neonatal rats.
Histol Histopathol 2011;26:13-21
22. Badri S, Dashti-Khavidaki S,
Lessan-Pezeshki M, Abdollahi M.
A review of the potential benefits of
pentoxifylline in diabetic and
non-diabetic proteinuria. J Pharm
Pharm Sci 2011;14:128-37
23. Farshchi A, Nikfar S, Abdollahi M.
Concerns on the use of chromium in
type 2 diabetes mellitus; needs to
conduct major meta-analysis.
Int J Pharmacol 2012;8:472
24. Ghamarian A, Abdollahi M, Su X, et al.
Effect of chicory seed extract on glucose
tolerance test (GTT) and metabolic
profile in early and late stage diabetic
rats. Daru 2012;20:56
25. Hasani-Ranjbar S, Larijani B,
Abdollahi M. A systematic review of
Iranian medicinal plants useful in
diabetes mellitus. Arch Med Sci
2008;4:285-92
26. Hasani-Ranjbar S, Larijani B,
Abdollahi M. Recent update on animal
and human evidences of promising
anti-diabetic medicinal plants:
a mini-review of targeting new drugs.
Asian J Anim Vet Adv 2011;6:1271-5
27. Hirsch IB. Insulin analogues. N Engl
J Med 2005;352:174-83
28. Khanavi M, Taheri M, Rajabi A, et al.
Stimulation of hepatic glycogenolysis and
inhibition of gluconeogenesis are the
mechanisms of antidiabetic effect of
Centaurea bruguierana ssp. belangerana.
Asian J Anim Vet Adv 2012;7:1166-74
29. Noor A, Bansal VS, Vijayalakshmi MA.
Current update on anti-diabetic
biomolecules from key traditional Indian
medicinal plants. Curr Sci
2013;104:721-5
30. Sarkhail P, Abdollahi M, Fadayevatan S,
et al. Effect of Phlomis persica on
glucose levels and hepatic enzymatic
antioxidants in streptozotocin-induced
diabetic rats. Pharmacogn Mag
2010;6:219-24
31. Nakai M, Sekiguchi F, Obata M, et al.
Synthesis and insulin-mimetic activities
of metal complexes with 3-
hydroxypyridine-2-carboxylic acid.
J Inorg Biochem 2005;99:1275-82
32. Sakurai H, Adachi Y. The pharmacology
of the insulinomimetic effect of zinc
complexes. Biometals 2005;18:319-23
33. Sanghera DK, Blackett PR.
Type 2 diabetes genetics: beyond gwas.
J Diabetes Metab 2012;3(189):6948
M. Safavi et al.
1356 Expert Opin. Drug Discov. (2013) 8(11)
Exp
ert O
pin.
Dru
g D
isco
v. D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Se
rial
s U
nit -
Lib
rary
on
11/0
4/13
For
pers
onal
use
onl
y.
34. Edelman SV. Type II diabetes mellitus.
Adv Intern Med 1998;43:449-500
35. Mercado MM, McLenithan JC,
Silver KD, Shuldiner AR. Genetics of
insulin resistance. Curr Diab Rep
2002;2:83-95
36. Goldstein BJ. Insulin resistance as the
core defect in type 2 diabetes mellitus.
Am J Cardiol 2002;90(5):3-10
37. Bloomgarden ZT. Insulin resistance:
current concepts. Clin Ther
1998;20:216-31
38. Watanabe RM. The genetics of insulin
resistance: where’s Waldo?
Curr Diab Rep 2010;10:476-84
39. Bastard JP, Maachi M, Lagathu C, et al.
Recent advances in the relationship
between obesity, inflammation, and
insulin resistance. Eur Cytokine Netw
2006;17:4-12
. A review that helps to understand the
pathophysiological mechanisms at the
root of insulin resistance and T2DM.
40. Look AHEAD Research Group.
Cardiovascular effects of intensive
lifestyle intervention in type 2 diabetes.
N Engl J Med 2013;369(2):145-54
41. Saeidi N, Meoli L, Nestoridi E, et al.
Reprogramming of intestinal glucose
metabolism and glycemic control in rats
after gastric bypass. Science
2013;341(6144):406-10
42. Das UN. Obesity, metabolic syndrome
X, and inflammation. Nutrition
2002;18:430-2
43. Cinti S, Mitchell G, Barbatelli G, et al.
Adipocyte death defines macrophage
localization and function in adipose
tissue of obese mice and humans.
J Lipid Res 2005;46:2347-55
44. Kroder G, Bossenmaier B, Kellerer M,
et al. Tumor necrosis factor-alpha- and
hyperglycemia-induced insulin resistance.
Evidence for different mechanisms and
different effects on insulin signaling.
J Clin Invest 1996;97:1471-7
45. Lagathu C, Bastard JP, Auclair M, et al.
Chronic interleukin-6 (IL-6) treatment
increased IL-6 secretion and induced
insulin resistance in adipocyte: prevention
by rosiglitazone. Biochem Biophys
Res Commun 2003;311:372-9
46. Pessin JE, Saltiel AR. Signaling pathways
in insulin action: molecular targets of
insulin resistance. J Clin Invest
2000;106:165-9
47. Taniguchi CM, Emanuelli B, Kahn CR.
Critical nodes in signalling pathways:
insights into insulin action. Nat Rev Mol
Cell Biol 2006;7:85-96
48. Walker RJ, Anderson NM, Jiang Y, et al.
Role of beta-adrenergic receptor
regulation of TNF-alpha and insulin
signaling in retinal Muller cells.
Invest Ophthalmol Vis Sci
2011;52:9527-33
49. Reiter CE, Wu X, Sandirasegarane L,
et al. Diabetes reduces basal retinal
insulin receptor signaling: reversal with
systemic and local insulin. Diabetes
2006;55:1148-56
50. White MF. IRS proteins and the
common path to diabetes. Am J Physiol
Endocrinol Metab 2002;283:413-22
51. Khan AH, Pessin JE. Insulin regulation
of glucose uptake: a complex interplay of
intracellular signalling pathways.
Diabetologia 2002;45:1475-83
52. Sasaoka T, Hori H, Wada T, et al.
SH2-containing inositol phosphatase
2 negatively regulates insulin-induced
glycogen synthesis in L6 myotubes.
Diabetologia 2001;44:1258-67
53. Sasaoka T, Wada T, Tsuneki H. Lipid
phosphatases as a possible therapeutic
target in cases of type 2 diabetes and
obesity. Pharmacol Ther
2006;112:799-809
54. Wada T, Sasaoka T, Funaki M, et al.
Overexpression of SH2-containing
inositol phosphatase 2 results in negative
regulation of insulin-induced metabolic
actions in 3T3-L1 adipocytes via its
5’-phosphatase catalytic activity.
Mol Cell Biol 2001;21:1633-46
55. Hotamisligil GS, Budavari A, Murray D,
Spiegelman BM. Reduced tyrosine kinase
activity of the insulin receptor in obesity-
diabetes. Central role of tumor necrosis
factor-alpha. J Clin Invest
1994;94:1543-9
56. Long SD, Pekala PH. Regulation of
GLUT4 mRNA stability by tumor
necrosis factor-alpha: alterations in both
protein binding to the 3’ untranslated
region and initiation of translation.
Biochem Biophys Res Commun
1996;220(3):949-53
57. Bastard JP, Maachi M, Van Nhieu JT,
et al. Adipose tissue IL-6 content
correlates with resistance to insulin
activation of glucose uptake both in vivo
and in vitro. J Clin Endocrinol Metab
2002;87(5):2084-9
58. Trayhurn P, Wood IS. Adipokines:
inflammation and the pleiotropic role of
white adipose tissue. Br J Nutr
2004;92:347-55
59. Kasuga M. Insulin resistance and
pancreatic beta cell failure. J Clin Invest
2006;116:1756-60
60. Cerf ME. Beta cell dysfunction and
insulin resistance.
Front Endocrinol (Lausanne) 2013;4:37
61. Prentki M, Nolan CJ. Islet beta cell
failure in type 2 diabetes. J Clin Invest
2006;116:1802-12
62. Poitout V, Robertson RP.
Glucolipotoxicity: fuel excess and
beta-cell dysfunction. Endocr Rev
2008;29:351-66
63. Xiang AH, Kawakubo M, Trigo E, et al.
Declining beta-cell compensation for
insulin resistance in Hispanic women
with recent gestational diabetes mellitus:
association with changes in weight,
adiponectin, and C-reactive protein.
Diabetes Care 2010;33:396-401
64. Faghihi T, Radfar M, Barmal M, et al.
A randomized, placebo-controlled trial of
selenium supplementation in patients
with type 2 diabetes: effects on glucose
homeostasis, oxidative stress, and lipid
profile. Am J Ther
2013;Published online 29 Apr 2013;
doi:10.1097/MJT.0b013e318269175f
65. Navaei-Nigjeh M, Rahimifard M,
Pourkhalili N, et al. Multi-organ
protective effects of cerium oxide
nanoparticle/selenium in diabetic rats:
evidence for more efficiency of
nanocerium in comparison to metal form
of cerium. Asian J Anim Vet Adv
2012;7:605-12
66. Tabatabaei-Malazy O, Larijani B,
Abdollahi M. A novel management of
diabetes by means of strong antioxidants’
combination. J Med Hypotheses Ideas
2013;7:25-30
67. Pourkhalili N, Hosseini A,
Nili-Ahmadabadi A, et al. Biochemical
and cellular evidence of the benefit of a
combination of cerium oxide
nanoparticles and selenium to diabetic
rats. World J Diabetes 2011;2:204-10
68. Drews G, Krippeit-Drews P, Dufer M.
Oxidative stress and beta-cell
dysfunction. Pflugers Arch
2010;460:703-18
Importance of synthetic drugs for T2DM drug discovery
Expert Opin. Drug Discov. (2013) 8(11) 1357
Exp
ert O
pin.
Dru
g D
isco
v. D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Se
rial
s U
nit -
Lib
rary
on
11/0
4/13
For
pers
onal
use
onl
y.
69. Abdollahi M, Fooladian F, Emami B,
et al. Protection by sildenafil and
theophylline of lead acetate-induced
oxidative stress in rat submandibular
gland and saliva. Hum Exp Toxicol
2003;22:587-92
70. Astaneie F, Afshari M, Mojtahedi A,
et al. Total antioxidant capacity and
levels of epidermal growth factor and
nitric oxide in blood and saliva of
insulin-dependent diabetic patients.
Arch Med Res 2005;36:376-81
71. Farshchi A, Nikfar S, Seyedifar M,
Abdollahi M. Effect of chromium on
glucose and lipid profiles in patients with
type 2 diabetes; a meta-analysis review of
randomized trials. J Pharm Pharm Sci
2013;16:99-114
72. Hosseini A, Abdollahi M. It is time to
formulate an antioxidant mixture for
management of diabetes and its
complications: notice for pharmaceutical
industries. Int J Pharm 2012;8:60-1
73. Kamyab S, Hejrati S, Khanavi M,
Mohammadirad A. Hepatic mechanisms
of the Walnut antidiabetic effect in mice.
Cent Eur J Biol 2010;5:304-9
74. Larijani B, Afshari M,
Astanehi-Asghari F, et al. Effect of
short-term carvedilol therapy on salivary
and plasma oxidative stress parameters
and plasma glucose level in type II
diabetes. Therapy 2006;3:119-23
75. Milani E, Nikfar S, Khorasani R, et al.
Reduction of diabetes-induced oxidative
stress by phosphodiesterase inhibitors in
rats. Comp Biochem Physiol C
Toxicol Pharmacol 2005;140:251-5
76. Mohseni Salehi Monfared SS, Larijani B,
Abdollahi M. Islet transplantation and
antioxidant management:
a comprehensive review.
World J Gastroenterol 2009;15:1153-61
77. Radfar M, Larijani B, Hadjibabaie M,
et al. Effects of pentoxifylline on
oxidative stress and levels of EGF and
NO in blood of diabetic type-2 patients;
a randomized, double-blind placebo-
controlled clinical trial.
Biomed Pharmacother 2005;59:302-6
78. Sarkhail P, Rahmanipour S,
Fadyevatan S, et al. Antidiabetic effect of
Phlomis anisodonta: effects on hepatic
cells lipid peroxidation and antioxidant
enzymes in experimental diabetes.
Pharmacol Res 2007;56:261-6
79. Vosough-Ghanbari S, Rahimi R,
Kharabaf S, et al. Effects of Satureja
khuzestanica on serum glucose, lipids and
markers of oxidative stress in patients
with type 2 diabetes mellitus:
a double-blind randomized controlled
trial. Evid Based Complement
Alternat Med 2010;7:465-70
80. Bolzano K. Biguanides: reasons for
withdrawal of drugs and remaining
indications. Acta Med Austriaca
1978;5:85-8
81. Luft D, Schmulling RM, Eggstein M.
Lactic acidosis in biguanide-treated
diabetics: a review of 330 cases.
Diabetologia 1978;14:75-87
82. Ansari G, Mojtahedzadeh M, Kajbaf F,
et al. How does blood glucose control
with metformin influence intensive
insulin protocols? Evidence for
involvement of oxidative stress and
inflammatory cytokines. Adv Ther
2008;25:681-702
83. Defronzo RA, Goodman AM. Efficacy of
metformin in patients with
non-insulin-dependent diabetes mellitus.
The Multicenter Metformin Study
Group. N Engl J Med 1995;333:541-9
84. Holman RR, Paul SK, Bethel MA, et al.
10-year follow-up of intensive glucose
control in type 2 diabetes. N Engl J Med
2008;359:1577-89
85. Morsink LM, Smits MM, Diamant M.
Advances in pharmacologic therapies for
type 2 diabetes. Curr Atheroscler Rep
2013;15:302
. Overview of recent advances in
pharmacological therapy for T2DM,
focusing on agents that recently have
been approved and those for which
approval is pending.
86. Bailey CJ, Turner RC. Metformin.
N Engl J Med 1996;334:574-9
87. Cusi K, Consoli A, Defronzo RA.
Metabolic effects of metformin on
glucose and lactate metabolism in
noninsulin-dependent diabetes mellitus.
J Clin Endocrinol Metab
1996;81:4059-67
88. Hundal RS, Krssak M, Dufour S, et al.
Mechanism by which metformin reduces
glucose production in type 2 diabetes.
Diabetes 2000;49:2063-9
89. Del Prato S, Marchetto S, Pipitone A,
et al. Metformin and free fatty acid
metabolism. Diabetes Metab Rev
1995;11:33-41
90. Stumvoll M, Nurjhan N, Perriello G,
et al. Metabolic effects of metformin in
non-insulin-dependent diabetes mellitus.
N Engl J Med 1995;333:550-4
91. Merrill GF, Kurth EJ, Hardie DG,
Winder WW. AICA riboside increases
AMP-activated protein kinase, fatty acid
oxidation, and glucose uptake in rat
muscle. Am J Physiol 1997;273:1107-12
92. Zhou G, Myers R, Li Y, et al. Role of
AMP-activated protein kinase in
mechanism of metformin action.
J Clin Invest 2001;108:1167-74
93. Palumbo PJ. Metformin: effects on
cardiovascular risk factors in patients
with non-insulin-dependent diabetes
mellitus. J Diabetes Complications
1998;12:110-19
94. Garber AJ, Duncan TG, Goodman AM,
et al. Efficacy of metformin in type II
diabetes: results of a double-blind,
placebo-controlled, dose-response trial.
Am J Med 1997;103:491-7
95. Sheehan MT. Current therapeutic
options in type 2 diabetes mellitus:
a practical approach. Clin Med Res
2003;1:189-200
. An informative review on the
management of T2DM from the
initiation of oral agents through dual
(potentially triple) therapy onto
insulin initiation.
96. Stang M, Wysowski DK, Butler-Jones D.
Incidence of lactic acidosis in metformin
users. Diabetes Care 1999;22:925-7
97. Stolar MW, Hoogwerf BJ, Gorshow SM,
et al. Managing type 2 diabetes: going
beyond glycemic control. J Manag
Care Pharm 2008;14:s2-19
98. Rendell MS, Kirchain WR.
Pharmacotherapy of type 2 diabetes
mellitus. Ann Pharmacother
2000;34:878-95
99. Bharatam PV, Patel DS, Iqbal P.
Pharmacophoric features of biguanide
derivatives: an electronic and structural
analysis. J Med Chem 2005;48:7615-22
100. Setter SM, Iltz JL, Thams J,
Campbell RK. Metformin hydrochloride
in the treatment of type 2 diabetes
mellitus: a clinical review with a focus on
dual therapy. Clin Ther
2003;25:2991-3026
101. Del Prato S, Pulizzi N. The place of
sulfonylureas in the therapy for
type 2 diabetes mellitus. Metabolism
2006;55:20-7
M. Safavi et al.
1358 Expert Opin. Drug Discov. (2013) 8(11)
Exp
ert O
pin.
Dru
g D
isco
v. D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Se
rial
s U
nit -
Lib
rary
on
11/0
4/13
For
pers
onal
use
onl
y.
102. Bryan J, Crane A, Vila-Carriles WH,
et al. Insulin secretagogues, sulfonylurea
receptors and K(ATP) channels.
Curr Pharm Des 2005;11:2699-716
103. Gribble FM, Reimann F. Differential
selectivity of insulin secretagogues:
mechanisms, clinical implications, and
drug interactions.
J Diabetes Complications 2003;17:11-15
104. Perfetti R, Ahmad A. Novel sulfonylurea
and non-sulfonylurea drugs to promote
the secretion of insulin.
Trends Endocrinol Metab
2000;11:218-23
105. Bak JF, Pedersen O. Gliclazide and
insulin action in human muscle.
Diabetes Res Clin Pract 1991;14(2):61-4
106. Pedersen O, Hother-Nielsen O, Bak J,
et al. Effects of sulfonylureas on
adipocyte and skeletal muscle insulin
action in patients with
non-insulin-dependent diabetes mellitus.
Am J Med 1991;90(6A):22-8
107. Korytkowski MT. Sulfonylurea treatment
of type 2 diabetes mellitus: focus on
glimepiride. Pharmacotherapy
2004;24:606-20
108. Jasik M. Glimepiride in daily practice.
Przegl Lek 2003;60:409-12
109. Basit A, Riaz M, Fawwad A.
Glimepiride: evidence-based facts, trends,
and observations (GIFTS). Vasc Health
Risk Manag 2012;8:463-72
110. Bijlstra PJ, Lutterman JA, Russel FG,
et al. Interaction of sulphonylurea
derivatives with vascular ATP-sensitive
potassium channels in humans.
Diabetologia 1996;39:1083-90
111. Lee TM, Chou TF. Impairment of
myocardial protection in type 2 diabetic
patients. J Clin Endocrinol Metab
2003;88:531-7
112. Campbell RK. Glimepiride: role of a
new sulfonylurea in the treatment of
type 2 diabetes mellitus.
Ann Pharmacother 1998;32:1044-52
113. Dornhorst A. Insulinotropic meglitinide
analogues. Lancet 2001;358:1709-16
114. Malaisse WJ. Pharmacology of the
meglitinide analogs: new treatment
options for type 2 diabetes mellitus.
Treat Endocrinol 2003;2:401-14
115. Li J, Tian H, Li Q, et al. Improvement
of insulin sensitivity and beta-cell
function by nateglinide and repaglinide
in type 2 diabetic patients - a
randomized controlled double-blind and
double-dummy multicentre clinical trial.
Diabetes Obes Metab 2007;9:558-65
116. Rosenstock J, Hassman DR,
Madder RD, et al. Repaglinide versus
nateglinide monotherapy: a randomized,
multicenter study. Diabetes Care
2004;27:1265-70
117. Hu S, Wang S, Fanelli B, et al.
Pancreatic beta-cell K(ATP) channel
activity and membrane-binding studies
with nateglinide: a comparison with
sulfonylureas and repaglinide.
J Pharmacol Exp Ther 2000;293:444-52
118. McLeod JF. Clinical pharmacokinetics of
nateglinide: a rapidly-absorbed,
short-acting insulinotropic agent.
Clin Pharmacokinet 2004;43:97-120
119. Chachin M, Yamada M, Fujita A, et al.
Nateglinide, a D-phenylalanine derivative
lacking either a sulfonylurea or
benzamido moiety, specifically inhibits
pancreatic beta-cell-type K(ATP) channels.
J Pharmacol Exp Ther
2003;304:1025-32
120. Campbell IW. Nateglinide–current and
future role in the treatment of patients
with type 2 diabetes mellitus. Int J
Clin Pract 2005;59:1218-28
121. Spencer CM, Markham A. Troglitazone.
Drugs 1997;54:89-101
122. Bae MA, Rhee H, Song BJ. Troglitazone
but not rosiglitazone induces G1 cell
cycle arrest and apoptosis in human and
rat hepatoma cell lines. Toxicol Lett
2003;139:67-75
123. Nolan JJ, Ludvik B, Beerdsen P, et al.
Improvement in glucose tolerance and
insulin resistance in obese subjects treated
with troglitazone. N Engl J Med
1994;331:1188-93
124. Suter SL, Nolan JJ, Wallace P, et al.
Metabolic effects of new oral
hypoglycemic agent CS-045 in NIDDM
subjects. Diabetes Care 1992;15:193-203
125. Yki-Jarvinen H. Thiazolidinediones.
N Engl J Med 2004;351:1106-18
126. Okuno A, Tamemoto H, Tobe K, et al.
Troglitazone increases the number of
small adipocytes without the change of
white adipose tissue mass in obese
Zucker rats. J Clin Invest
1998;101:1354-61
127. Picard F, Auwerx J. PPAR (gamma) and
glucose homeostasis. Annu Rev Nutr
2002;22:167-97
128. Defronzo RA. Banting Lecture. From the
triumvirate to the ominous octet: a new
paradigm for the treatment of
type 2 diabetes mellitus. Diabetes
2009;58:773-95
129. Maeda N, Takahashi M, Funahashi T,
et al. PPARgamma ligands increase
expression and plasma concentrations of
adiponectin, an adipose-derived protein.
Diabetes 2001;50:2094-9
130. Matsuda M, Shimomura I, Sata M, et al.
Role of adiponectin in preventing
vascular stenosis. The missing link of
adipo-vascular axis. J Biol Chem
2002;277:37487-91
131. Phillips LS, Grunberger G, Miller E,
et al. Once- and twice-daily dosing with
rosiglitazone improves glycemic control
in patients with type 2 diabetes.
Diabetes Care 2001;24:308-15
132. Park KS, Ciaraldi TP, Abrams-Carter L,
et al. Troglitazone regulation of glucose
metabolism in human skeletal muscle
cultures from obese type II diabetic
subjects. J Clin Endocrinol Metab
1998;83:1636-43
133. Idris I, Gray S, Donnelly R.
Rosiglitazone and pulmonary oedema:
an acute dose-dependent effect on human
endothelial cell permeability.
Diabetologia 2003;46:288-90
134. Page RL, Gozansky WS, Ruscin JM.
Possible heart failure exacerbation
associated with rosiglitazone: case report
and literature review. Pharmacotherapy
2003;23:945-54
135. Papoushek C. The “glitazones”:
rosiglitazone and pioglitazone. J Obstet
Gynaecol Can 2003;25:853-7
136. Gim HJ, Cheon YJ, Ryu JH, Jeon R.
Design and synthesis of benzoxazole
containing indole analogs as peroxisome
proliferator-activated receptor-gamma/
delta dual agonists. Bioorg Med
Chem Lett 2011;21:3057-61
137. Matsumoto K, Yano M, Miyake S, et al.
Effects of voglibose on glycemic
excursions, insulin secretion, and insulin
sensitivity in non-insulin-treated
NIDDM patients. Diabetes Care
1998;21:256-60
138. Shinozaki K, Suzuki M, Ikebuchi M,
et al. Improvement of insulin sensitivity
and dyslipidemia with a new
alpha-glucosidase inhibitor, voglibose, in
nondiabetic hyperinsulinemic subjects.
Metabolism 1996;45:731-7
Importance of synthetic drugs for T2DM drug discovery
Expert Opin. Drug Discov. (2013) 8(11) 1359
Exp
ert O
pin.
Dru
g D
isco
v. D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Se
rial
s U
nit -
Lib
rary
on
11/0
4/13
For
pers
onal
use
onl
y.
139. Scheen AJ. Is there a role for
alpha-glucosidase inhibitors in the
prevention of type 2 diabetes mellitus?
Drugs 2003;63:933-51
140. Johnston PS, Lebovitz HE, Coniff RF,
et al. Advantages of alpha-glucosidase
inhibition as monotherapy in elderly
type 2 diabetic patients. J Clin
Endocrinol Metab 1998;83:1515-22
141. Balfour JA, McTavish D. Acarbose.
An update of its pharmacology and
therapeutic use in diabetes mellitus.
Drugs 1993;46:1025-54
142. Santeusanio F, Compagnucci P.
A risk-benefit appraisal of acarbose in the
management of non-insulin-dependent
diabetes mellitus. Drug Saf
1994;11:432-44
143. Reuser AJ, Wisselaar HA. An evaluation
of the potential side-effects of
alpha-glucosidase inhibitors used for the
management of diabetes mellitus. Eur J
Clin Invest 1994;24(3):19-24
144. Geng P, Qiu F, Zhu Y, Bai G. Four
acarviosin-containing oligosaccharides
identified from Streptomyces
coelicoflavus ZG0656 are potent
inhibitors of alpha-amylase.
Carbohydr Res 2008;343:882-92
145. van Genugten RE, van Raalte DH,
Diamant M. Does glucagon-like peptide-
1 receptor agonist therapy add value in
the treatment of type 2 diabetes? Focus
on exenatide. Diabetes Res Clin Pract
2009;86(Suppl 1):S26-34
146. Parks M, Rosebraugh C. Weighing risks
and benefits of liraglutide–the FDA’s
review of a new antidiabetic therapy.
N Engl J Med 2010;362:774-7
147. Nikfar S, Abdollahi M, Salari P. The
efficacy and tolerability of exenatide in
comparison to placebo; a systematic
review and meta-analysis of randomized
clinical trials. J Pharm Pharm Sci
2012;15:1-30
148. Nauck MA, Baranov O, Ritzel RA,
Meier JJ. Do current incretin mimetics
exploit the full therapeutic potential
inherent in GLP-1 receptor stimulation?
Diabetologia
2013;published online 9 Jun 2013;
doi:10.1007/s00125-013-2953-6
149. Drucker DJ, Nauck MA. The incretin
system: glucagon-like peptide-1 receptor
agonists and dipeptidyl
peptidase-4 inhibitors in type 2 diabetes.
Lancet 2006;368:1696-705
150. Holst JJ. The physiology of glucagon-like
peptide 1. Physiol Rev 2007;87:1409-39
151. Pospisilik JA, Stafford SG, Demuth HU,
et al. Long-term treatment with the
dipeptidyl peptidase IV inhibitor P32/
98 causes sustained improvements in
glucose tolerance, insulin sensitivity,
hyperinsulinemia, and beta-cell glucose
responsiveness in VDF (fa/fa) Zucker
rats. Diabetes 2002;51:943-50
152. Cho YM, Merchant CE, Kieffer TJ.
Targeting the glucagon receptor family
for diabetes and obesity therapy.
Pharmacol Ther 2012;135(3):247-78
153. Siu FY, He M, de Graaf C, et al.
Structure of the human glucagon class B
G-protein-coupled receptor. Nature
2013;499(7459):444-9
154. Garber AJ. Long-acting glucagon-like
peptide 1 receptor agonists: a review of
their efficacy and tolerability.
Diabetes Care 2011;34(Suppl 2):S279-84
155. Bond A. Exenatide (Byetta) as a novel
treatment option for type 2 diabetes
mellitus. Proc (Bayl Univ Med Cent)
2006;19:281-4
156. Parkes DG, Pittner R, Jodka C, et al.
Insulinotropic actions of exendin-4 and
glucagon-like peptide-1 in vivo and in
vitro. Metabolism 2001;50:583-9
157. Bjerre KL, Madsen LW, Andersen S,
et al. Glucagon-like Peptide-1 receptor
agonists activate rodent thyroid C-cells
causing calcitonin release and C-cell
proliferation. Endocrinology
2010;151:1473-86
158. Franks AS, Lee PH, George CM.
Pancreatitis: a potential complication of
liraglutide? Ann Pharmacother
2012;46:1547-53
159. Wajcberg E, Amarah A. Liraglutide in
the management of type 2 diabetes.
Drug Des Devel Ther 2010;4:279-90
160. Augeri DJ, Robl JA, Betebenner DA,
et al. Discovery and preclinical profile of
Saxagliptin (BMS-477118): a highly
potent, long-acting, orally active
dipeptidyl peptidase IV inhibitor for the
treatment of type 2 diabetes.
J Med Chem 2005;48:5025-37
161. Gallwitz B. Small molecule
dipeptidylpeptidase IV inhibitors under
investigation for diabetes mellitus
therapy. Expert Opin Investig Drugs
2011;20:723-32
162. Saisho Y, Itoh H. Dipeptidyl
peptidase-4 inhibitors and angioedema:
a class effect? Diabet Med
2013;30:149-50
163. Zhu L, Li Y, Qiu L, et al. Design and
synthesis of 4-(2,4,5-Trifluorophenyl)
butane-1,3-diamines as Dipeptidyl
Peptidase IV Inhibitors. ChemMedChem
2013;8:1104-16
164. Kim W, Egan JM. The role of incretins
in glucose homeostasis and diabetes
treatment. Pharmacol Rev
2008;60:470-512
165. Holst JJ, Vilsboll T, Deacon CF. The
incretin system and its role in
type 2 diabetes mellitus.
Mol Cell Endocrinol 2009;297:127-36
166. Mentlein R, Gallwitz B, Schmidt WE.
Dipeptidyl-peptidase IV hydrolyses
gastric inhibitory polypeptide,
glucagon-like peptide-1(7-36)amide,
peptide histidine methionine and is
responsible for their degradation in
human serum. Eur J Biochem
1993;214:829-35
167. Someya Y, Tahara A, Nakano R, et al.
Pharmacological profile of ASP8497, a
novel, selective, and competitive
dipeptidyl peptidase-IV inhibitor, in vitro
and in vivo. Naunyn Schmiedebergs
Arch Pharmacol 2008;377:209-17
168. Gupta R, Walunj SS, Tokala RK, et al.
Emerging drug candidates of dipeptidyl
peptidase IV (DPP IV) inhibitor class for
the treatment of Type 2 Diabetes.
Curr Drug Targets 2009;10:71-87
169. Scheen A. Gliptins (dipeptidyl
peptidase-4 inhibitors) and risk of acute
pancreatitis. Expert Opin Drug Saf
2013;12(4):545-57
170. Lankas GR, Leiting B, Roy RS, et al.
Dipeptidyl peptidase IV inhibition for
the treatment of type 2 diabetes:
potential importance of selectivity over
dipeptidyl peptidases 8 and 9. Diabetes
2005;54:2988-94
171. Babu A. Canagliflozin for the treatment
of type 2 diabetes. Drugs Today (Barc)
2013;49:363-76
172. Ghosh RK, Ghosh SM, Chawla S,
Jasdanwala SA. SGLT2 inhibitors: a new
emerging therapeutic class in the
treatment of type 2 diabetes mellitus.
J Clin Pharmacol 2012;52:457-63
173. Gerich JE. Role of the kidney in normal
glucose homeostasis and in the
hyperglycaemia of diabetes mellitus:
therapeutic implications. Diabet Med
2010;27:136-42
M. Safavi et al.
1360 Expert Opin. Drug Discov. (2013) 8(11)
Exp
ert O
pin.
Dru
g D
isco
v. D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Se
rial
s U
nit -
Lib
rary
on
11/0
4/13
For
pers
onal
use
onl
y.
174. Wright EM, Hirayama BA, Loo DF.
Active sugar transport in health and
disease. J Intern Med 2007;261:32-43
175. Rahmoune H, Thompson PW,
Ward JM, et al. Glucose transporters in
human renal proximal tubular cells
isolated from the urine of patients with
non-insulin-dependent diabetes. Diabetes
2005;54:3427-34
176. Neumiller JJ, White JR Jr,
Campbell RK. Sodium-glucose
co-transport inhibitors: progress and
therapeutic potential in type 2 diabetes
mellitus. Drugs 2010;70:377-85
177. Elkinson S, Scott LJ. Canagliflozin: first
global approval. Drugs 2013;73:979-88
178. Hardman TC, Dubrey SW.
Development and potential role of
type-2 sodium-glucose transporter
inhibitors for management of
type 2 diabetes. Diabetes Ther
2011;2:133-45
179. Nomura S, Sakamaki S, Hongu M, et al.
Discovery of canagliflozin, a novel
C-glucoside with thiophene ring, as
sodium-dependent glucose cotransporter
2 inhibitor for the treatment of
type 2 diabetes mellitus. J Med Chem
2010;53:6355-60
180. Bays HE, Goldberg RB, Truitt KE,
Jones MR. Colesevelam hydrochloride
therapy in patients with type 2 diabetes
mellitus treated with metformin: glucose
and lipid effects. Arch Intern Med
2008;168:1975-83
181. Keche Y. Bromocriptine mesylate: food
and Drug Administration approved new
approach in therapy of non-insulin
dependent diabetes mellitus with poor
glycemic control. J Pharm Bioallied Sci
2010;2:148-50
182. Kumar KA, Kumar SP, Janardan S.
Bromocriptine: a novel approach for
management of type 2 diabetes mellitus.
JDDT 2012;2:151-5
183. Via MA, Chandra H, Araki T, et al.
Bromocriptine approved as the first
medication to target dopamine activity to
improve glycemic control in patients
with type 2 diabetes. Diabetes Metab
Syndr Obes 2010;3:43-8
184. Green BD, Flatt PR, Bailey CJ.
Dipeptidyl peptidase IV (DPP IV)
inhibitors: a newly emerging drug class
for the treatment of type 2 diabetes.
Diab Vasc Dis Res 2006;3:159-65
185. Inzucchi SE, McGuire DK. New drugs
for the treatment of diabetes: part II:
incretin-based therapy and beyond.
Circulation 2008;117:574-84
186. Rummey C, Metz G. Homology models
of dipeptidyl peptidases 8 and 9 with a
focus on loop predictions near the active
site. Proteins 2007;66:160-71
187. Edmondson SD, Mastracchio A,
Duffy JL, et al. Discovery of potent and
selective orally bioavailable
beta-substituted phenylalanine derived
dipeptidyl peptidase IV inhibitors.
Bioorg Med Chem Lett
2005;15:3048-52
188. Xu J, Wei L, Mathvink R, et al.
Discovery of potent and selective
phenylalanine based dipeptidyl peptidase
IV inhibitors. Bioorg Med Chem Lett
2005;15:2533-6
189. Duffy JL, Kirk BA, Wang L, et al.
4-aminophenylalanine and
4-aminocyclohexylalanine derivatives as
potent, selective, and orally bioavailable
inhibitors of dipeptidyl peptidase IV.
Bioorg Med Chem Lett
2007;17:2879-85
190. Chen P, Caldwell CG, Mathvink RJ,
et al. Imidazopiperidine amides as
dipeptidyl peptidase IV inhibitors for the
treatment of diabetes. Bioorg Med
Chem Lett 2007;17:5853-7
191. Cho TP, Gang LZ, Long YF, et al.
Synthesis and biological evaluation of
bicyclo[3.3.0] octane derivatives as
dipeptidyl peptidase 4 inhibitors for the
treatment of type 2 diabetes. Bioorg Med
Chem Lett 2010;20:3521-5
192. Furuta S, Smart C, Hackett A, et al.
Pharmacokinetics and metabolism of
[14C]anagliptin, a novel dipeptidyl
peptidase-4 inhibitor, in humans.
Xenobiotica 2013;43:432-42
193. Kato N, Oka M, Murase T, et al.
Discovery and pharmacological
characterization of N-[2-({2-[(2S)-2-
cyanopyrrolidin-1-yl]-2-oxoethyl}amino)-
2-methylpropyl]-2-methyl pyrazolo[1,5-a]
pyrimidine-6-carboxamide hydrochloride
(anagliptin hydrochloride salt) as a
potent and selective DPP-IV inhibitor.
Bioorg Med Chem 2011;19:7221-7
194. Yoshida T, Akahoshi F, Sakashita H,
et al. Fused bicyclic
heteroarylpiperazine-substituted
L-prolylthiazolidines as highly potent
DPP-4 inhibitors lacking the electrophilic
nitrile group. Bioorg Med Chem
2012;20:5033-41
.. Example of original report of the
design of new DPP-4 inhibitors
according to previous structure-based
screening techniques.
195. Nabeno M, Akahoshi F, Kishida H,
et al. A comparative study of the binding
modes of recently launched dipeptidyl
peptidase IV inhibitors in the active site.
Biochem Biophys Res Commun
2013;434:191-6
.. A study describing co-crystal structure
of vildagliptin with DPP-4 and the
relationships between six inhibitors
binding interactions with DPP-4 and
their inhibitory activity.
196. Magnin DR, Robl JA, Sulsky RB, et al.
Synthesis of novel potent dipeptidyl
peptidase IV inhibitors with enhanced
chemical stability: interplay between the
N-terminal amino acid alkyl side chain
and the cyclopropyl group of alpha-
aminoacyl-l-cis-4,5-methanoprolinenitrile-
based inhibitors. J Med Chem
2004;47:2587-98
197. Yoshida T, Akahoshi F, Sakashita H,
et al. Discovery and preclinical profile of
teneligliptin (3-[(2S,4S)-4-[4-(3-methyl-
1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]
pyrrolidin-2-y lcarbonyl]thiazolidine):
a highly potent, selective, long-lasting
and orally active dipeptidyl peptidase IV
inhibitor for the treatment of
type 2 diabetes. Bioorg Med Chem
2012;20:5705-19
198. Sakashita H, Akahoshi F, Kitajima H,
et al. [(S)-gamma-(Arylamino)prolyl]
thiazolidine compounds as a novel series
of potent and stable DPP-IV inhibitors.
Bioorg Med Chem 2006;14:3662-71
199. Sakashita H, Akahoshi F, Yoshida T,
et al. Lead optimization of [(S)-gamma-
(arylamino)prolyl]thiazolidine focused on
gamma-substituent: indoline compounds
as potent DPP-IV inhibitors.
Bioorg Med Chem 2007;15:641-55
200. Yoshida T, Sakashita H, Akahoshi F,
Hayashi Y. [(S)-gamma-(4-Aryl-1-
piperazinyl)-l-prolyl]thiazolidines as a
novel series of highly potent and
long-lasting DPP-IV inhibitors.
Bioorg Med Chem Lett
2007;17:2618-21
201. Cox JM, Harper B, Mastracchio A, et al.
Discovery of 3-aminopiperidines as
potent, selective, and orally bioavailable
dipeptidyl peptidase IV inhibitors.
Importance of synthetic drugs for T2DM drug discovery
Expert Opin. Drug Discov. (2013) 8(11) 1361
Exp
ert O
pin.
Dru
g D
isco
v. D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Se
rial
s U
nit -
Lib
rary
on
11/0
4/13
For
pers
onal
use
onl
y.
Bioorg Med Chem Lett
2007;17:4579-83
202. Eckhardt M, Langkopf E, Mark M, et al.
8-(3-(R)-aminopiperidin-1-yl)-7-but-2-
ynyl-3-methyl-1-(4-methyl-quinazolin-2-
ylme thyl)-3,7-dihydropurine-2,6-dione
(BI 1356), a highly potent, selective,
long-acting, and orally bioavailable
DPP-4 inhibitor for the treatment of
type 2 diabetes. J Med Chem
2007;50:6450-3
203. Eckhardt M, Hauel N, Himmelsbach F,
et al. 3,5-Dihydro-imidazo[4,5-d]
pyridazin-4-ones: a class of potent
DPP-4 inhibitors. Bioorg Med
Chem Lett 2008;18:3158-62
204. Brigance RP, Meng W, Fura A, et al.
Synthesis and SAR of azolopyrimidines
as potent and selective dipeptidyl
peptidase-4 (DPP4) inhibitors for
type 2 diabetes. Bioorg Med Chem Lett
2010;20:4395-8
205. Parmee ER, He J, Mastracchio A, et al.
4-Amino cyclohexylglycine analogues as
potent dipeptidyl peptidase IV inhibitors.
Bioorg Med Chem Lett 2004;14:43-6
206. Chen P, Caldwell CG, Ashton W, et al.
Synthesis and evaluation of [(1R)-1-
amino-2-(2,5-difluorophenyl)ethyl]
cyclohexanes and 4-[(1R)-1-amino-2-
(2,5-difluorophenyl)ethyl]piperidines as
DPP-4 inhibitors. Bioorg Med
Chem Lett 2011;21:1880-6
207. Maezaki H, Banno Y, Miyamoto Y, et al.
Discovery of potent, selective, and orally
bioavailable quinoline-based dipeptidyl
peptidase IV inhibitors targeting Lys554.
Bioorg Med Chem 2011;19:4482-98
208. Ikuma Y, Hochigai H, Kimura H, et al.
Discovery of 3H-imidazo[4,5-c]quinolin-
4(5H)-ones as potent and selective
dipeptidyl peptidase IV (DPP-4)
inhibitors. Bioorg Med Chem
2012;20:5864-83
209. Kinne RK, Castaneda F. SGLT
inhibitors as new therapeutic tools in the
treatment of diabetes.
Handb Exp Pharmacol
2011(203):105-26
210. Kipp H, Kinne-Saffran E, Bevan C,
Kinne RK. Characteristics of renal Na
(+)-D-glucose cotransport in the skate
(Raja erinacea) and shark (Squalus
acanthias). Am J Physiol
1997;273:R134-42
211. Kurosaki E, Ogasawara H. Ipragliflozin
and other sodium-glucose cotransporter-2
(SGLT2) inhibitors in the treatment of
type 2 diabetes: preclinical and clinical
data. Pharmacol Ther 2013;139:51-9
212. Isaji M. SGLT2 inhibitors: molecular
design and potential differences in effect.
Kidney Int Suppl 2011;S14-19
213. Imamura M, Nakanishi K, Suzuki T,
et al. Discovery of Ipragliflozin
(ASP1941): a novel C-glucoside with
benzothiophene structure as a potent and
selective sodium glucose co-transporter 2
(SGLT2) inhibitor for the treatment of
type 2 diabetes mellitus.
Bioorg Med Chem 2012;20:3263-79
214. Meng W, Ellsworth BA, Nirschl AA,
et al. Discovery of dapagliflozin:
a potent, selective renal
sodium-dependent glucose cotransporter
2 (SGLT2) inhibitor for the treatment of
type 2 diabetes. J Med Chem
2008;51:1145-9
215. Chen ZH, Wang RW, Qing FL.
Synthesis and biological evaluation of
SGLT2 inhibitors:
gem-difluoromethylenated Dapagliflozin
analogs. Tetrahedron Lett
2012;53:2171-6
216. Yao CH, Song JS, Chen CT, et al.
Discovery of novel N-beta-D-
xylosylindole derivatives as
sodium-dependent glucose cotransporter
2 (SGLT2) inhibitors for the
management of hyperglycemia in
diabetes. J Med Chem 2011;54:166-78
217. Yao CH, Song JS, Chen CT, et al.
Synthesis and biological evaluation of
novel C-indolylxylosides as
sodium-dependent glucose co-transporter
2 inhibitors. Eur J Med Chem
2012;55:32-8
218. Ikegai K, Imamura M, Suzuki T, et al.
Synthesis and biological evaluation of
C-glucosides with azulene rings as
selective SGLT2 inhibitors for the
treatment of type 2 diabetes mellitus:
discovery of YM543. Bioorg Med Chem
2013;21:3934-48
219. Chen CH, Lee O, Yao CN, et al. Novel
azulene-based derivatives as potent
multi-receptor tyrosine kinase inhibitors.
Bioorg Med Chem Lett
2010;20:6129-32
220. Rekka E, Chrysselis M, Siskou I,
Kourounakis A. Synthesis of new azulene
derivatives and study of their effect on
lipid peroxidation and lipoxygenase
activity. Chem Pharm Bull (Tokyo)
2002;50:904-7
221. Zhang LY, Yang F, Shi WQ, et al.
Synthesis and antigastric ulcer activity of
novel 5-isoproyl-3,8-dimethylazulene
derivatives. Bioorg Med Chem Lett
2011;21:5722-5
222. Mascitti V, Maurer TS, Robinson RP,
et al. Discovery of a clinical candidate
from the structurally unique dioxa-
bicyclo[3.2.1]octane class of
sodium-dependent glucose cotransporter
2 inhibitors. J Med Chem
2011;54:2952-60
223. Mascitti V, Robinson RP, Preville C,
et al. Syntheses of C-5-spirocyclic.
C-glycoside SGLT2 inhibitors.
Tetrahedron Lett 2010;51:1880-3
224. Vyas VK, Bhatt HG, Patel PK, et al.
CoMFA and CoMSIA studies on C-aryl
glucoside SGLT2 inhibitors as potential
anti-diabetic agents. SAR QSAR
Environ Res 2013;24:519-51
.. The study explores ligand-based 3D
QSAR (CoMFA and CoMSIA) on C-
aryl glucoside SGLT2 inhibitors as
potential anti-diabetic agents.
225. Wu JS, Peng YH, Wu JM, et al.
Discovery of non-glycoside sodium-
dependent glucose co-transporter 2
(SGLT2) inhibitors by ligand-based
virtual screening. J Med Chem
2010;53:8770-4
226. Sheridan C. SGLT2 inhibitors race to
enter type-2 diabetes market.
Nat Biotechnol 2012;30:899-900
227. Shing TK, Ng WL, Chan JY, Lau CB.
Design, syntheses, and sar studies of
carbocyclic analogues of sergliflozin as
potent sodium-dependent glucose
cotransporter 2 inhibitors. Chem Int
Ed Engl
2013;published online 19 Jun 2013;
doi:10.1002/anie.201302543
228. Gao Y, Zhao G, Liu W, et al.
Thiadiazole-based thioglycosides as
sodium-glucose co-transporter 2 (sglt2)
inhibitors. Chin J Chem 2010;28:605-12
229. Liao C, Sitzmann M, Pugliese A,
Nicklaus MC. Software and resources for
computational medicinal chemistry.
Future Med Chem 2011;3:1057-85
230. Liu L, Ma Y, Wang RL, et al. Find
novel dual-agonist drugs for treating
type 2 diabetes by means of
cheminformatics. Drug Des Devel Ther
2013;7:279-88
231. Kitada M, Kume S, Kanasaki K, et al.
Sirtuins as possible drug targets in
M. Safavi et al.
1362 Expert Opin. Drug Discov. (2013) 8(11)
Exp
ert O
pin.
Dru
g D
isco
v. D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Se
rial
s U
nit -
Lib
rary
on
11/0
4/13
For
pers
onal
use
onl
y.
type 2 diabetes. Curr Drug Targets
2013;14:622-36
232. Milne JC, Lambert PD, Schenk S, et al.
Small molecule activators of SIRT1 as
therapeutics for the treatment of
type 2 diabetes. Nature 2007;450:712-16
233. Kun S, Nagy GZ, Toth M, et al.
Synthesis of variously coupled conjugates
of D-glucose, 1,3,4-oxadiazole, and
1,2,3-triazole for inhibition of glycogen
phosphorylase. Carbohydr Res
2011;346:1427-38
234. Panzhinskiy E, Ren J, Nair S.
Pharmacological inhibition of protein
tyrosine phosphatase 1B: a promising
strategy for the treatment of obesity and
type 2 diabetes mellitus.
Curr Med Chem 2013;20:2609-25
235. Patel D, Jain M, Shah SR, et al.
Discovery of potent, selective and orally
bioavailable triaryl-sulfonamide based
PTP1B inhibitors. Bioorg Med
Chem Lett 2012;22:1111-17
236. Lipska KJ, Bailey CJ, Inzucchi SE. Use
of metformin in the setting of
mild-to-moderate renal insufficiency.
Diabetes Care 2011;34:1431-7
237. Becic F, Kapic E, Becic E.
Glimepiride--an oral antidiabetic agent.
Med Arh 2003;57:125-7
238. Clissold SP, Edwards C. Acarbose.
A preliminary review of its
pharmacodynamic and pharmacokinetic
properties, and therapeutic potential.
Drugs 1988;35:214-43
239. Madsbad S. Liraglutide effect and action
in diabetes (LEAD�) trial. Expert Rev
Endocrinol Metab 2009;4:119-29
240. Panina G. The DPP-4 inhibitor
vildagliptin: robust glycaemic control in
type 2 diabetes and beyond.
Diabetes Obes Metab 2007;9:32-9
241. Rosenstock J, Aggarwal N, Polidori D,
et al. Dose-ranging effects of
canagliflozin, a sodium-glucose
cotransporter 2 inhibitor, as add-on to
metformin in subjects with
type 2 diabetes. Diabetes Care
2012;35:1232-8
244. Barnett A. DPP-4 inhibitors and their
potential role in the management of
type 2 diabetes. Int J Clin Pract
2006;60:1454-70
245. Tahrani AA, Piya MK, Barnett AH.
Saxagliptin: a new DPP-4 inhibitor for
the treatment of type 2 diabetes mellitus.
Adv Ther 2009;26:249-62
243. Kim D, Wang L, Beconi M, et al. (2R)-
4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro
[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl]-
1-(2,4,5-trifluorophenyl)butan-2-amine:
a potent, orally active dipeptidyl
peptidase IV inhibitor for the treatment
of type 2 diabetes. J Med Chem
2005;48:141-51
246. Villhauer EB, Brinkman JA, Naderi GB,
et al. 1-[[(3-hydroxy-1-adamantyl)amino]
acetyl]-2-cyano-(S)-pyrrolidine: a potent,
selective, and orally bioavailable
dipeptidyl peptidase IV inhibitor with
antihyperglycemic properties.
J Med Chem 2003;46:2774-89
247. Feng J, Zhang Z, Wallace MB, et al.
Discovery of alogliptin: a potent,
selective, bioavailable, and efficacious
inhibitor of dipeptidyl peptidase IV.
J Med Chem 2007;50:2297-300
248. Thomas L, Eckhardt M, Langkopf E,
et al. (R)-8-(3-amino-piperidin-1-yl)-7-
but-2-ynyl-3-methyl-1-(4-methyl-
quinazolin-2-ylm ethyl)-3,7-dihydro-
purine-2,6-dione (BI 1356), a novel
xanthine-based dipeptidyl peptidase
4 inhibitor, has a superior potency and
longer duration of action compared with
other dipeptidyl peptidase-4 inhibitors.
J Pharmacol Exp Ther 2008;325:175-82
242. Metzler WJ, Yanchunas J, Weigelt C,
et al. Involvement of DPP-IV catalytic
residues in enzyme-saxagliptin complex
formation. Protein Sci 2008;17:240-50
249. Katsuno K, Fujimori Y, Takemura Y,
et al. Sergliflozin, a novel selective
inhibitor of low-affinity sodium glucose
cotransporter (SGLT2), validates the
critical role of SGLT2 in renal glucose
reabsorption and modulates plasma
glucose level. J Pharmacol Exp Ther
2007;320:323-30
AffiliationMaliheh Safavi1, Alireza Foroumadi1 &
Mohammad Abdollahi†1,2
†Author for correspondence1Tehran University of Medical Sciences,
Faculty of Pharmacy and Pharmaceutical Sciences
Research Center, Tehran, Iran2Professor and Dean, Tehran University of
Medical Sciences, Faculty of Pharmacy and
pharmaceutical Sciences Research Center,
Department of Toxicology and Pharmacology,
Tehran 1417614411, Iran
E-mail: [email protected]
Importance of synthetic drugs for T2DM drug discovery
Expert Opin. Drug Discov. (2013) 8(11) 1363
Exp
ert O
pin.
Dru
g D
isco
v. D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Se
rial
s U
nit -
Lib
rary
on
11/0
4/13
For
pers
onal
use
onl
y.