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Cardiovascular (CV) DrugsRohan Merchant Baran Group Meeting09/01/2018
What are Cardiovascular Diseases (CVDs)?■ Diseases of the heart■ Vascular diseases of the brain■ Diseases of blood vessels.
1. CVDs due to atherosclerosis: ■ ischaemic heart disease or coronary artery disease (e.g. heart attack) ■ cerebrovascular disease (e.g. stroke) ■ diseases of the aorta and arteries, including hypertension and peripheral vascular disease
2. Other CVDs ■ congenital heart disease ■ rheumatic heart disease ■ cardiomyopathies ■ cardiac arrhythmias
Some Background
In Atherosclerosis, fatty material and cholesterol are deposited inside the lumen of medium- and large-sized blood vessels (arteries). These deposits (plaques) cause the inner surface of the blood vessels to become irregular and the lumen to become narrow, making it harder for blood to flow through. Blood vessels also become less pliable as a result. Eventually, the plaque can rupture, triggering the formation of a blood clot. If the blood clot develops in a coronary artery, it can cause a heart attack; if it develops in the brain, it can cause a stroke.
Behavioural Risk Factors: tobacco use, physical inactivity, unhealthy diet, alcohol abuseMetabolic Risk Factors:• Raised Blood Pressure (hypertension)• Raised Blood Sugar (diabetes)• Raised Blood Lipids (cholesterol) - Not included in todays presentation• Overweight and ObesityOther Risk Factors: income, education, age, genetic, psychological
Cardiomyopathy makes it harder for the heart to pump blood to the rest of your body. The main types of cardiomyopathy include dilated, hypertrophic (thickening of heart muscle) and restrictive cardiomyopathy. It can lead to heart failure, blood clots, valve problems and cardiac arrest.
Risk Factors: high blood pressure, tissue damage from heart attack, valve problems, obesity
Rheumatic heart disease is caused by damage to the heart muscle and heart valves from rheumatic fever, following a streptococcal pharyngitis/tonsillitis.
The heart valves can remain stretched and/or scarred, and normal blood flow through damaged valves is interrupted. Blood may flow backward through stretched valves that do not close properly, or may be blocked due to scarred valves not opening properly. When the heart is damaged in this way, the heart valves are unable to function adequately, and heart surgery may be required. Untreated, RHD causes heart failure and those affected are at risk of arrhythmias, stroke, endocarditis and complications of pregnancy.
Once the acute illness has gone away, patients need to take penicillin, or an equivalent antibiotic, for many years to prevent recurrences. This is a very important treatment because the risk of heart valve damage increases if rheumatic fever recurs.
Malformations of heart structures present at birth are known as congenital heart defects. They may be caused by: (i) a close blood relation between parents (consanguinity); (ii) maternal infections (e.g. rubella); (iii) maternal use of alcohol and drugs (e.g. warfarin); and (iv) poor maternal nutrition (e.g. deficiency of folic acid). In some cases the cause remains unknown. Examples of congenital heart disease include holes in the septum of the heart, abnormal valves and abnormalities in heart chambers. It is the most common birth defect and was present in 48.9 million people globally (2015).
Cardiac arrhythmias occur when the electrical impulses that coordinate your heartbeats don't work properly, causing your heart to beat too fast, too slow or irregularly. They are classified as tachycardia (resting heart rate > 100 beats/min) and bradycardia (resting heart rate < 60 beats/min).
Atrial fibrillation is one of the common tachyarrhythmias arising from the atria. It is characterized by predominantly uncoordinated atrial activation with consequent deterioration of mechanical function of the heart. Atrial fibrillation increases the risk of stroke fivefold. Once atrial fibrillation is diagnosed, drugs are given to control the heart rate and anticoagulants are given to prevent stroke.
It can be caused by coronary artery disease, high blood pressure, drugs, alcohol abuse, electrolyte imbalance, diabetes.
■ Biggest cause of deaths worldwide (17 million in 2008)■ 40–59 year olds: ca. 40% people with CVD■ 60–79 year olds: ca. 70% people with CVD■ 80% of CVD deaths due to stroke and heart attack
Major causes of deaths Distribution of CVD deathsGlobal atlas on cardiovascular disease prevention and control (WHO)http://www.who.int/cardiovascular_diseases/publications/atlas_cvd/en/
https://www.mayoclinic.org/diseases-conditions/cardiomyopathy/symptoms-causes/syc-20370709
https://www.rhdaustralia.org.au/what-rheumatic-heart-disease
https://www.mayoclinic.org/diseases-conditions/heart-arrhythmia/symptoms-causes/syc-20350668
Classes of CV Drugs Covered in this GM:■ Anticoagulants (blood thinners)■ Antiplatelet medications■ Cardiac glycosides■ Diuretics■ Beta blockers■ Calcium channel blockers■ Angiotensin-converting enzyme (ACE) inhibitors■ Angiotensin receptor blockersNot Covered in this GM: ■ Cholesterol lowering drugs■ CV devices
Antithrombotic drugs
10 most important risk factors for all deaths
(6%)
(13%)
(5%)
Cardiovascular (CV) DrugsRohan Merchant Baran Group Meeting09/01/2018
Anticoagulants: They're given to people at a high risk of getting clots, to reduce their chances of developing serious conditions such as strokes, heart attacks, deep vein thrombosis and, pulmonary embolism.
Selected Anticoagulants on the Market:
O
OH
Ph
Me
O
Owarfarin
1948: rat poison1954: approved for medical use
(most commonly prescribed, ca. 40% maket share)
Vitamin K anatagonists (VKAs)Administration: Oral or IV
OO
HOOH
OOdicoumarol (NP)
1941: first coumarin anticoagulant
O
Ophenindione
Approved in 1950s(rarely used)
OO
O
HO3SOOH
O
NHSO3HHO2C
OH
OSO3HO
heparinnatural gylcosaminoglycanUsed medically since 1937
Injected into veinmade from pig intestinesantithrombin III agonist
Avg MW 12-15 kDa1 unit of heparin (Howell unit) =
0.002 mg of protein
Novel Oral Anticoagulants (NOACs)Rapid onset and offset of action, no strong drug or food interactions, less frequent monitoring and re-dosing (1/day)
Direct Factor Xa Inhibitors (no antidote)
N
N
OO
NH
OO
O
SClrivaroxaban (Xarelto®)
Bayer/J&J, 2011 FDA AprrovalFirst oral direct Xa inhibitor$5.64 billion (2017 sales)
NMe2O
NH HN
OS
NMeN
O
O
NH
N Cl
edoxaban (Savasya®)Daiichi Sankyo, 2011 (Japan) 2015 (US)
NH
O
MeOO
HN
N Cl
NH
NMe2
betrixaban (Bevyxxa®)Portola, 2017 (US)
N
NNO
H2N
O
N
OMe
Oapixaban (Eliquis®)
Pfizer/BMS, 2012 (EU), 2014 (US)$4.87 billion (2017 sales)
N
NMe
HNO
N
N
NH2
OnhexO
EtO2CN
dabigatran etexilate (Pradaxa®)BI, 2008 (EU), 2010 (US)Direct thrombin inhibitor
Antithrombotic Drugs (anticoagulants and antiplatelet drugs)
How do they work and why are they different?
• Fibrin and platelets most important components of a thrombus (clot) • Fibrin is a protein that forms a mesh that traps red blood cells• Platelets, a type of blood cell, form clumps that add to the mass of the thrombus • Both fibrin and platelets stabilize the thrombus and prevent it from falling apart • Fibrin is the more important component of clots that form in veins• Platelets are the more important component of clots that form in arteries
Anticoagulants slow down clotting, thereby reducing fibrin formation and preventing clots from forming and growing. Antiplatelet agents prevent platelets from clumping and also prevent clots from forming and growing.
see GM:Natural products inspired
drug discovery (Chu, 2017)
Example for Anticoagulant Factor Xa (FXa) is essential in formation of thrombin, a key mediator of both fibrin formation and platelet activation. Inhibition of FXa interrupts both the intrinsic and extrinsic activation pathways of thrombin production. FXa together with FVa, calcium, and phospholipids, a prothrombinase complex is formed, which converts prothrombin to thrombin. Thrombin, in turn, converts fibrinogen to fibrin and activates platelets, eventually leading to the formation of thrombus or blood clots. This process involves signal amplification, with one molecule of FXa activating many molecules of prothrombin to thrombin. Therefore, inhibition of FXa may be more effective than inhibition of thrombin.
https://en.wikipedia.org/wiki/Coagulation
Cardiovascular (CV) DrugsRohan Merchant Baran Group Meeting09/01/2018
N
NNO
H2N
O
N
OMe
O
apixaban (Eliquis®)Pfizer/BMS, 2012 (EU), 2014 (US)
4.87 billion (2017 sales)FXa Ki = 0.08 nM
J. Med. Chem. 2007, 50, 5339
SA862, FXa Ki = 0.15 nMThrombin Ki = 2000 µM
Bioorg. Med. Chem. Lett. 2000, 10, 685highly basic benzamidine (poor oral bioavailibility)
H2N
HN
N O
HN
OCO2H
NOStarting Point (Screening)
FXa Ki = 38.5 µM
H2N
NH N O
MeO2C
O
HN
NH2
NH
FXa Ki = 94 nMThrombin Ki = 16 µM
Bioorg. Med. Chem. Lett. 1997, 7, 2813dibasic compound (poor adsorption & PK),
ester instability
FXa Ki = 0.52 nMThrombin Ki = 400 µM
Bioorg. Med. Chem. Lett. 1998, 8, 3143Bioorg. Med. Chem. Lett. 1999, 9, 1195
J. Med. Chem. 1999, 42, 2752J. Med. Chem. 1999, 42, 2760
H2N
NH N O
N
O
HN
H2NO2SNN
N
H2N
NH N O O
HN
H2NO2S
isoxazole overlayed with the pyrazle analog(allows for substitution at 3-position)
NH2
NN
CF3HN
O
F
SO2Me
DPC423, FXa Ki = 0.15 nMBioorg. Med. Chem. Lett. 2000, 10, 685
Phase Iamidine analog (30x more potent in vitro,
<5% oral bioavailibility)J. Med. Chem. 2001, 44, 566
•TFApKa ~8.8
pKa ~10.7razaxaban, FXa Ki = 0.19 nM
Phase II (Proof-of-concept trial)J. Med. Chem. 2003, 46, 4405J. Med. Chem. 2005, 48, 1729
(invivo hydrolysis to primary aniline)
NN
CF3HN
O
F
N
NO
H2N
improves selectivity,poor solubility, permeability
N
NMe2
less lipophilicheterocycle
Review of FXa Inhibitors:J. Med. Chem. 2010, 53, 6243
razaxaban and apixaban overlayed
NNN
O
OEtO
I
MeO
HNO
1. CuI, phen2. NH3
16%(2 steps)
MeO
NH2
MeO
NHN
90%
N
O
Name Rxn
NO I
+Cl
CO2Et
1. Et3N2. TFA
71%(2 steps)
NH2
I
1. 5-Br valeryl chloride2. KOtBu3. PCl54. Li2CO35. morpholine
10%(5 steps)
DX-9065a (Initial Benchmark)Selective FXa inhibitor (IC50 41 nM)
No thrombin inhibition (conc > 2000 µM)Daiichi Pharmaceutical Company
J. Med. Chem. 1994, 37, 1200
H2N
NH
CO2H
ON
Me
NH
Evolution of apixaban (Eliquis®) as direct factor Xa inhibitor
NaNO2, HCl;A, NaOAc,
EtOH
Me
O
ClOEt
O
A MedChem Route
Cardiovascular (CV) DrugsRohan Merchant Baran Group Meeting09/01/2018
Antiplatelet Drugs
Heart attack, chest pain (angina), strokes, transient ischemic attacks (little strokes)They are effective in the arterial circulation, where anticoagulants have little effect
CO2HOAc aspirin
1980– (for CV)
COX inhibitor (thromboxane A2 antagonist)CO2H
OAc
F3C
triflusal1981 (Spain)
Adenosine diphosphate (ADP) receptor inhibitors (P2Y12 antagonist)
N
SCl
ticlopidine (Ticlid®)Sanofi, 1978 (France), 1991 (US)first in class thienopyridine drug
N
SCl
O OMe
clopidogrel (Plavix®)Sanofi, 1998 (US)
$1.70 bllion (2017 sales)
N
SF
O
OAcPrasugrel (Effient®)Daiichi Sankyo/Eli Lilly
2009 (US)
HO OH
O N
NN
N
N
S
HN
Me
F
F
ticagrelor (Brilinta®)AstraZeneca, 2011 (US)
OH
O
HO OH
NO
N
N
N
S CF3
HNSMe
POOO
PO O
HHP
Cl Cl
HOOHO
cangrelor (Kengreal®)Medicines Company,
2015 (US)
NH
O
N NN
N
O
cilostazol (Pletaal®)Otsuka, 1999 (US)
phosphodiesterase inhibitor
O
H
H H
H
EtO2CHNO
Me
N
F
vorapaxar(Zontivity®)
Merck, 2014 (US)Protease-activated receptor-1 (PAR-1)
antagonist
O
NH
O OH
HN
S OO
tirofiban (Aggrastat®)Medicure Pharma,
2010 (US)GP IIb/IIIa inhibitors
HNNH
HN
HN
NH
OO O
OHO
O
S S
HN
H2N
OO
N
O
Me
eptifibatide (Integrilin®)Gylcoprotein (GP) IIb/IIIa inhibitors
NN
NN
N
NN
N OH
OHHO
HO
dipyridamole (Persantine®)adenosine reuptake inhibitor
HNNH2
HN
HO OH
O N
NN
N
N
S
HN
Me
F
F
ticagrelor (Brilinta®)AstraZeneca, 2011 (US)
orally bioavailable
OH
O
HO OH
NO
N
N
N
NH2
POOO
POO O
HHPHO
OHOATP (pIC50 = 3.5)
natural antagonist (starting point)
Synthesis of ticagrelor (Bioorg. Med. Chem. Lett. 2007, 17, 6013)
med chem
HO
OF
F
1. SOCl22. sultam
80%(2 steps)
N
OF
FS
MeMe
O O
1. CH2N2, Pd(OAc)22. LiOH
50%
HO2C F
F
1. ClCO2Et2. NaN33. toluene, Δ4. HCl5. L-tartaric acid62% (5 steps)
H2N F
F•tartaric acid
Name Rxn
A
OH
OAc
(Boc)2NNa,Pd(PPh3)4
92%
OH
N(Boc)2
1. OsO42. HCl
96%(2 steps)
OH
NH2
HO
HO
1. DMP, H+2. CBzCl HO NHCBz
O O
Me Me
82%(2 steps)
ca. $125/g(Oakwood) 1. tBuOK,
BrCH2CH2OAc2. LiBH43. H2, Pd/C
85%(3 steps)
O NH2
O O
Me Me
HO
NNCl
SMe
H2N Cl
+DIPEA75%
O NH
O O
Me Me
N
NCl
H2N S
Me
HO
O N
O O
Me Me
NN
N N
Cl
S
OH
Me
1. A, DIPEA2. TFA
89%ticagrelor
(AZD6140)
isoamyl-nitrite 88%
triazolopyrimidine>100X fold
10x
Cardiovascular (CV) DrugsRohan Merchant Baran Group Meeting09/01/2018
O
H
H H
H
EtO2CHNO
Me
N
F
vorapaxar (Zontivity®)Merck, 2014 (US)Protease-activated receptor-1 (PAR-1)
antagonist
O
H
H H
H
O
Me
NMe
Me(+)-himbacine
investigated for Alzheimers11-step LLS total synthesis
(chemists at Schering-Plough)Natural Product PAR-1 inactive
J. Am. Chem. Soc. 1996, 118, 9812
(analogs from racemic
synthesis)O
H
H H
H
O
Me
N
Me
high-throughputscreening
(±) IC50 = 300 nM(+) IC50 = 150 nM (ent-NP)
(–) IC50 = 1500 nMJ. Med. Chem. 2005, 48, 5884
Me
OH
Me
OTHPMe
OH
CO2Bn
Me
OH
BnO2C
DHP, H+
100%
1. BuLi, BnCOCl2. TsOH
71%(2 steps)
Lindlar cat.,H2
93%
BrO
OO O 1. PPh3, Br22. (CH2OH)2, H+
O
O
61% (2 steps)
HO2COMe
O1. [Pd],
2. NaOH70% (2 steps)
+
DCC77%
O
OO
O
Me
BnO2C
xylene,215 ºC48%
O
O
HCO2Bn
O
O
Me
H
H
DBU99%O
O
HCO2Bn
O
O
Me
H
H
1. Pd/C, H22. PtO2, H2
O
O
HCO2H
O
O
Me
H
H
HSOCl2;
Bu3SnH, Pd(PPh3)4
48%O
O
HCHO
O
O
Me
H
H
H 1. HWE2. H+
O
H
O
O
Me
H
H
H
N
F
J. Med. Chem. 2007, 50, 129J. Med. Chem. 2008, 51, 3061
1. Ti(OiPr)4, NH32. NaBH3CN3. EtOCOCl
51%(3 steps)
vorapaxarUS and Canadian commercial rights acquired by Aralez Pharma in 2016
Beta Blockers
Medications for hypertension and to manage abnormal heart rhythms. They reduce blood pressure by blocking the effects of adrenaline. The heart beats more slowly and with less force, thereby reducing blood pressure. Additionaly, they also act as vasodilators.
While once a first-line treatment for hypertension, they are not as effective as diuretics, ACE inhibitors, or calcium channel blockers, and were downgraded in June 2006 to fourth-in-line (UK). Additionally, at usual doses they carry an unacceptable risk of provoking type 2 diabetes.
Banned by IOC (lower heart rate and reduce tremors) → used by surgeons
Beta receptors are found on cells of the heart muscles, smooth muscles, airways, arteries, kidneys, and other tissues that are part of the sympathetic nervous system and lead to stress responses, especially when they are stimulated by adrenaline. Beta blockers interfere with the binding to the receptor of adrenaline and other stress hormones, and weaken the effects of stress hormones.
O
OHiPrHN
carvedilol(Coreg®)Roche, 1995 (US)
NH
OHO
NH
OMeO
propranolol (Inderal®)AZ, 1965 (US)
first commercial β-blockerdeveloper James Black won
1988 Nobel Prize in medicine
O
OHtBuHN
HO
HO
nadolol (Corgard®)
O O
HO
iPrHN
oxprenolol(Trasacor®)
OHO NHiPr
HN
pindolol (Visken®)Sandoz,1977 (US)
S NN
NO OH
O
timolol(Betimol®)1978 (US)
NHMs
HONHiPr
sotalol(Betapace®)
NH O
Me
OOH
NHiPrOnPr
acebutolol (Sectral®)
OOH
NHiPrO
H2Natenolol (Tenormin®)
1976 (UK)>20 β-Blockers Commercialized
NHtBu
NC NH2
O S2Cl2,DMF, rt40-60% N
SN
OHCl
NSN
OCl
HO NHtBu
timolol
HOOH
NHtBuA
from glyceradehyde
1. TsCl2. NaH, A
Synthesis of Timolol (Merck)
morpholine
J. Org. Chem. 1967, 32, 2823J. Org. Chem. 1976, 41, 3121
Cardiovascular (CV) DrugsRohan Merchant Baran Group Meeting09/01/2018
Calcium Channel Blockers (CCBs)
• Medications that disrupt the movement of calcium (Ca2+) through calcium channels.• Used as antihypertensive drugs• Particularly effective against large vessel stiffness, one of the common causes of elevated systolic blood pressure in elderly patients• Used to alter heart rate, to prevent cerebral vasospasm, and to reduce chest pain caused by angina pectoris (reduced blood flow to the heart)
• By acting on vascular smooth muscle, they reduce contraction of the arteries and cause an increase in arterial diameter, a phenomenon called vasodilation (CCBs do not work on venous smooth muscle)• By acting on cardiac muscles (myocardium), they reduce the force of contraction of the heart• By slowing down the conduction of electrical activity within the heart, they slow down the heart beat.• By blocking the calcium signal on adrenal cortex cells, they directly reduce aldosterone production, which correlates to lower blood pressure.
Hypertension, elevated blood pressure indicated by systolic or diastolic pressures exceeding 140 mmHg or 90 mmHg, respectively, is becoming an increasingly important medical problem as the general population becomes older and more overweight. A recent summary of research in the area of hypertension indicates that 50 million Americans and as many as one billion people globally suffer from hypertension (NHLBI, www.nhlbi.nih.gov, 2007). More importantly, the treatment of hypertension is becoming more complicated as the population ages, because many patients will take drugs to treat conditions such as diabetes, rheumatoid arthritis, atherosclerosis, and so on
NH
Me Me
MeO2C CO2MeNO2
nifedipine (Adalat®)Bayer, 1975 (US)
first commercial CCB
>15 dihydropyridineCCBs commercialized
NH
Me Me
MeO2C CO2EtCl
Cl
felodipine (Plendil®)AZ, 1988 (US)
(R) 1000x > (S) sold racemic
NH
Me
MeO2C CO2EtCl
O NH3
PhSO3
amlodipine besylate(Norvasc®)
Pfizer, 1988 (US)
CNMe
MeMeO
MeO
MeN OMe
OMeverpamil, 1981 (US)phenylalkylamine
N
S
O
OAc
OMe
diltiazem (Cardizem®)1982 (US)
benzothiazepine
N N
F
Fflunarizine(Sibelium®)
Ph
Me2N
In the body's tissues, the concentration of calcium ions (Ca2+) outside of cells is about 10000-fold higher than the concentration inside of cells. Embedded in the membrane of some cells are calcium channels. When these cells receive a certain signal, the channels open, letting calcium rush into the cell. The resulting increase in intracellular calcium has different effects in different types of cells. CCBs prevent or reduce the opening of these channels and thereby reduce these effects.
CCBs used as medications primarily have four effects:
Selected CCBs on the market
Commercial Synthesis of Diltiazem
SH
NH2O
RO2C
OMe
+toluene,
Δ
NH2
S
OH
OMe
CO2Rsteps,
chiral resolution
diltiazemUS4590188
(1986)(racemic)
SHNH2
OHNH4OH,
(NH4)2SO3,150 ºC
NH2
Ac2O,NaHCO3,
90 ºCNameRxn
76%(2 steps)
NHAc
S2Cl2,AcOH,80 ºC
NSS
ClNaHCO3,
rt
naphthothiazathiolium chloride
84%(2 steps)
NHSS
O
naphthodithiazole
NaOH,50 ºC90%
Route by Roche(Synthesis 1990, 6, 539)
A
Analogues at Roche
commercial
NameRxn
OMe
CHO
+
PhO
O
NaH,70 ºC
Name Rxn
PhO
O
O
OMe
54%,2:1 dr
desired pdtdirectly crystallizes
A, toluene,Δ; HCl
NH2
S OH
OMe
CO2R*
98%
1. NaOH2. H+, Δ
81%(2 steps)
HN
S
O
OH
OMe
>90% auxiliary recovered and reused
2 steps
Cl
Process Route by Roche(J. Org. Chem. 1992, 57, 851)
N
S
O
OAcMe2N
OMe
naltiazem(clinical candidate)more active analog
of diltiazem
OPhMgBr,
CuCl
(racemic)
Ph
OH
1. ClCH2COCl2. lipase Amano P-30 Ph
OH(–)84%
Ph
O+ O
Cl
auxiliary synthesis
Cardiovascular Diseases (CVDs)Rohan Merchant Baran Group Meeting09/01/2018
Angiotensin-Converting-Enzyme (ACE) Inhibitor
Treatment of hypertension, heart failure and after a heart attack (taken for life once started)
Relaxes blood vessels and decreases blood volume → lower pressure and decreased oxygen demand from the heart
• Inhibits ACE which is an important component of the renin-angiotensin system (hormone system that regulates blood pressure and fluid balance). • ACE catalyses the formation of angiotensin II from its precursor, angiotensin I• Angiotensin II is a powerful vasoconstrictor and increases blood pressure
N
O OHO
MeHS
captopril (Capoten®)BMS 1981 (US)
first ACE inhibitorthiol believed to cause rash and metallic taste
N
O OHOH
N
MeEtO
O
Ph
enalapril (Vasotec®)Merck, 1984 (US)Merck’s first billion dollar drug (1988)
N
O OHOH
N
MeEtO
O
Ph H H
ramipril (Altace®)Sanofi, 1991 (US)
N
OHN
MeEtO
O
Ph
quinapril (Accupril®)Pfizer, 1991 (US)
OHO
N
O OHOH
NHO
O
Ph
NH2
lisinopril (Zestril®)Merck/AZ, 1987 (US)
$1.2 billion (1999 sales)
HNEtO
O
Ph
NO
OH
O
benazepril (Lotensin®)Novartis, 1992 (US)
N
O OHOH
N
MeEtO
O
Ph H H
trandolapril (Mavik®)Abbott, 2006 (US)
NN
OOHO
HN
O
EtOPh
cilazapril (Inhibace®)Roche
N
O OHO
PO
OiPr
OEt
O
Phfosinopril (Monopril®)
BMS, 1991 (US)phosphinic acid Zn binding element
Cee, V.; Olhava, E. Leading ACE inhibitors for hypertensionThe Art of Drug Synthesis, 2007, Wiley & Sons
https://onlinelibrary.wiley.com/doi/pdf/10.1002/9780470134979.ch10
thiol ligand for active-site zinc ion and proline optimal C-terminal inhibitory residue
Pharmacological Paramters of ACE Inhibitors
Proposed binding of Ang I and early inhibitors to ACE
Br
H2NO
OMe
HO
+K2CO3 HN
OMeO
OH36% N
I
O
OMe
OBnO1. BnOCOCl2. I2, PPh3
41%(2 steps)
*
mixture of diastereomers(ratio not reported)
Bu3SnH,AIBN88%
NO
OMe
OBnO
H
HHN
O
OH
H
HN
O
OBn
OBnO
H
H Ti(OiPr)4,BnOH44%
diastereomersseparated 1.3:1 dr
H2,Pd/C91%
(1 step)
(7 step synthesis)
ramipril
Synthesis of Ramipril US5011940 (1987)
HN
OH
OO
Med Chem Route?1. MeOH, H+
2. NaBH4HN
OHO NO
OPhPhCHO,
pTsOH NOO
Ph
86%>20:1 dr 4
LDA
Br
>20:1 dr *
1. LAH2. H2, Pd/C
65% (3 steps)
HN
OHHN
O
OH
4
1. CbzCl2. Jones [O]3. H2, Pd/C
78% (3 steps)
J. Org. Chem. 1986, 51, 3140
Process RouteHN
OH
O
HO
1. BzCl2. MeOH, H+
3. MsOH, PPh3, DIAD, Et3N4. NaOH
HN
OH
O
MsO 84% (4 steps)
AlCl3,C6H6
BzN
OH
O
75%(100 kg) Bz cleavage &
hydrogenation
US4912231 (1990)Tetrahedron 1990, 31, 1241
Ph
50% H3PO2,AIBN, Δ
93%Ph
PO
OHH
CO2HClHMDS, TMSCl
82%Ph
PO
OHCO2H
Name RxnTet. Lett. 1984, 25, 4737
Org. Process Res. Dev. 1997, 1, 211Org. Process Res. Dev. 1997, 1, 315
fosinopril
Fosinopril Synthesis
Name Rxn
Cardiovascular (CV) DrugsRohan Merchant Baran Group Meeting09/01/2018
Angiotensin-Receptor Blockers (ARBs)
• AT1 receptors promote aldosterone secretion and Na retention by stimulation of angiotension receptors present on the adrenal cortex → elevated blood pressure due to vasoconstriction• AT2 receptors are present only in low levels and not associated with CV homeostasis.• The final step of the renin angiotensin cascade is the activation of angiotensin II receptors AT1 and AT2 by angiotensin II. • ACE inhibitors suppress RAS by blocking the formation of angiotensin II• Until 1995, ACE inhibitors only drugs capable of the RAS blockade (undesirable side effects such as a dry cough) • Angiotensin II AT1 receptor blockers more direct way to develop specific inhibitors of the RAS • Blocks the pathway more specifically than ACE inhibitors
NHNN
NN
NCl
HOnBu
losartan (Cozaar®)Merck, 1995 (US)
first ARB
NHNN
NN
O nBu
CO2H
Me
Mevalsartan (Diovan®)Novartis, 1997 US)
multi-billiondollar drugs
NHNN
NN
N O
nBu
irbesartan(Avapro®)
Sanofi/BMS,1998 (US)
[O] to acid by P450,
20x more active NnBu
CO2HS
HO2C •MsOH
eprosartan mesylate(Teveten®)
GSK, 1997 (US)
N
NnPr
Me
HO2CMeN
N telmisartan(Micardis®)
BI, 1999 (US)
NHNN
N1. Ph3CCl, Et3N2. nBuLi, B(OiPr)3; NH4Cl90% (2 steps)
NCPh3
NNN
(HO)2BH2N
CO2H
nBu OMe
NH+MeOH,
H2OnBu NH
NH
HO2CN
NH
nBuOHC
ClPOCl3,DMF55%
(2 steps)+
Br
Br
K2CO3
N
NnBuOHC
Cl
Br
NaBH490%
(2 steps)
N
NnBu
Cl
Br
HO
A
1. A, [Pd]2. H2SO4
88%(2 steps)
losartan
NameRxn
Merck Process Route for Losartan (J. Org. Chem. 1994, 59, 6391)
Me CNHCl,
MeOH NH
OMe72%
NH2
MeO2C
+NameRxn
93%Et3N
nBu
NH
NH
CO2Me
Br CHO
OH pTsOH,iPrOH
Br CHO
OiPr
A
A, K2CO3
N
N CHOnBu
MeO2C
Me
52%
SCO2H
EtO2C+
piperidine,110 ºC
N
NnBu
MeO2C
40%
CO2Et
S1. NaOH2. MsOH
70%(2 steps)
eprosartanmesylate
J. Med. Chem. 1992, 35, 3858J. Med. Chem. 1993, 36, 1880J. Org. Chem. 1997, 62, 8449
Perspective on Angiotensin-Receptor Blockers (ARB):
J. Med. Chem. 1996, 39, 625
NHNN
NN
N
OO
OEt
MeO
OO
candesartan cilexetil(Atacand®)
Takeda/AZ, 1998 (US)
Synthesis of Eprosartan Mesylate
NameRxn
Cardiovascular (CV) DrugsRohan Merchant Baran Group Meeting09/01/2018
Hypertension, elevated blood pressure indicated by systolic or diastolic pressures exceeding 140 mmHg or 90 mmHg, respectively, is becoming an increasingly important medical problem as the general population becomes older and more overweight. A recent summary of research in the area of hypertension indicates that 50 million Americans and as many as one billion people globally suffer from hypertension (NHLBI, www.nhlbi.nih.gov, 2007). More importantly, the treatment of hypertension is becoming more complicated as the population ages, because many patients will take drugs to treat conditions such as diabetes, rheumatoid arthritis, atherosclerosis, and so on
Diuretics (Water Pills)
• Helps rid your body of salt (sodium) and water• Makes kidneys release more sodium into urine and sodium takes water with it from blood• Decreases the amount of fluid flowing through blood vessels, reducing pressure on vessel walls
The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommends that most people try thiazide diuretics first to treat high blood pressure and heart problems related to high blood pressure.
In addition, also prescribed for heart failure, liver failure, tissue swelling (edema) and certain kidney disorders, such as kidney stones
S NH
NCl
OOSH2N
O O
chlorothiazide (Diuril®)Merck, 1957 (US)first drug of class
Thiazide and thiazide-like diuretics (>10 commercialized)Inhibits the sodium-chloride symporter leading to retention of water in the urine. Frequent urination is due to the increased loss of water that has not been retained from the body as a result of a concomitant relationship with sodium loss from the convoluted tubule.
Cl
SH2N
O O HN
OH
Ochlortalidone (Hygroton®)
Novartis, 1960 (US)
S NH
HNCl
OOSH2N
O Odihydrochlorothiazide
(Apo-hydro®)
NH
ClSNH2O
O
O
NMe
indapamide
Loop diureticsInhibit the body's ability to reabsorb sodium at the ascending loop in the nephron, which leads to an excretion of water in the urine, whereas water normally follows sodium back into the extracellular fluid.
HN SNH2
OO
Cl
HO2C
O
furosemide (Lasix®)1962 (US)
HO2C S NH2
O O
OPhNHMe
bumetanide (Bumex®)
ClCl
OO
OH
OEt
ethacrynic acid (Edecrin®)
Potassium-sparing diureticsPotassium is retained and not as much is lost into the urine as with other diuretics.
N
NCl
H2N NH2
N
O
NH2
NH2
amiloride (Midamor®)
Merck, 1981 (US)
OMeO
H OMe
O
Me
O
H
Oeplerenone (Inspra®)Pfizer (Pharmacia),
2002 (US)
OMeO
HSAc
Me
O
H
H
H
spironolactone(Aldactone®) 1950s–
N
N
NN
Ph
NH2H2N
triamtrene(Dyrenium®)
Cl
NH2
ClSO3H,150 ºC Cl NH2
ClO2S SO2Cl
Cl NH2
H2NO2S SO2NH2
NH3 HCONH2 chloro-thiazide
N
N
Synthesis of Amyloride (Med-Chem Route)O
O
OHH2N
H2NOH
N
N OHN
NOH
OMe
NH2N
NO
1. NaOH2. MeOH, H+
1. SO2Cl22. NH3
63%(2 steps)
OMe
NH2N
NO
Cl
H2N
H2N
NH
NH2amylorideJ. Med. Chem. 1965, 8, 638J. Med. Chem. 1967, 10, 66
3,5-diaminouracil
eplerenone
Review on synthesis of other spironolactone derivatives
Steroids 2017, 118, 76
O
Me
H
H
H
O
OMe
O
Me
H
H
H
O
OMeAspergillus
ochraceus HO
canrenone
O
Me
H
H
H
O
OMeHO
Me Me
CNHO Et3N, LiCl
NC
NH2
O
Me
H
H
H
O
OMeHO
NC
O
HCl,H2O
O
Me
H
H
H
O
OMeHO
CO2Me
NaOMe,MeOH
1. MsCl2. HCO2K
O
Me H
H
O
OMe
CO2Me
H2O2,Cl3CN,
K2HPO4
7Other methods of installing C-7 Carbon by Pfizer:
Pd carbonylation (Synlett 2008, 418)Furan 1,6-addition/oxidative cleavage
to carboxylic acid (Org. Lett. 2006, 8, 2111)
Synthesis of Chlorothiazide (J. Am. Chem. Soc. 1957, 79, 2028)
Synthesis of Eplerenone WO1997021720A2 (Pharmacia)
Cardiovascular (CV) DrugsRohan Merchant Baran Group Meeting09/01/2018
Hypertension, elevated blood pressure indicated by systolic or diastolic pressures exceeding 140 mmHg or 90 mmHg, respectively, is becoming an increasingly important medical problem as the general population becomes older and more overweight. A recent summary of research in the area of hypertension indicates that 50 million Americans and as many as one billion people globally suffer from hypertension (NHLBI, www.nhlbi.nih.gov, 2007). More importantly, the treatment of hypertension is becoming more complicated as the population ages, because many patients will take drugs to treat conditions such as diabetes, rheumatoid arthritis, atherosclerosis, and so on
Cardiac Glycosides
Family of compounds derived from the foxglove plant (Digitalis purpurea)
Increase the output force of the heart and decrease its rate of contractions by acting on the cellular sodium-potassium ATPase pump.
Treatments for congestive heart failure and cardiac arrhythmias Relative toxicity prevents them from being widely used.
sugar end of the steroid can alter the molecule’s solubility and kinetics
R
Osugar
general structure
OOR =
OO
bufadienolides(mainly TCM)
cardenolides
Me
OHH
HOHO
OH
H
O
OHOMe
HO
HOOH
OO
ouabain(Strodival®)
Me
OH
HMe
H
HOO
OHO
Me
OO
R
O
HOO
OMe
MeHO
HO
R = OH; digoxin (Lanoxin®) GSK, 1954 (US)R = H; digitoxin (Digitaline®)
According to GSK, farmers in the Netherlands grow fields of woolly foxglove, which is a member of the snapdragon family. Bales of dried foxglove leaves are shipped to the U.S. Here, processing facilities macerate the leaves and extract digitalis using an aqueous-alcohol solvent. Further treatment and processing yields powdered digoxin, which is compounded into tablets, injectable solutions, elixirs, and capsules. It takes about 1,000 kg of dried foxglove leaves to make 1 kg of pure digoxin, the company adds.
https://pubs.acs.org/cen/coverstory/83/8325/8325digoxin.html
‘The cardiac drug digoxin, in use for more than 200 years, stemmed from an herbal remedy rather than from laboratory chemistry. English physician William Withering is credited with discovering in 1775 that the foxglove plant could help those suffering from abnormal fluid buildup, or dropsy, as it was called in those days.
In a 1785 report, Withering writes that he was asked to evaluate a home remedy for dropsy compounded by Mrs. Hutton, "an old woman in Shropshire." Her herbal concoction "made cures after the more regular practitioners had failed," according to his report.
Withering, who was also a botanist, quickly figured out that of the 20 or so herbs in the woman's remedy, foxglove was the key ingredient. In his report, he noted that foxglove was particularly helpful for his patients who developed dropsy after suffering from scarlet fever or bad sore throats. Scarlet fever and strep throat, both caused by a Streptococcus bacterium, can damage the heart valves. Improperly functioning valves can lead to congestive heart failure--a condition in which fluid builds up in the body's tissues because of the heart's weak pumping action.Withering used dried foxglove leaves in his dropsy remedy. The leaves contain a number of glycosides--chemicals that are composed of a sugar and a cardenolide (which has a five-membered lactone ring)--that are called by the umbrella term digitalis. The flowers, seeds, and sap also contain digitalis, but less than the leaves have.’
Cl
ClO
N
CO2Htafamidis (Vyndaqel®)
Pfizer, 2011 (EU)familial amyloid cardiomyopathy
NH
O OH
O
Me
O
EtO NNH
NNN
CO2H
Me MeO
Me
sacbutril(neprilysin inhibtor)
valsartan(ARB)
Entresto® (sacbutril:valsartan 1:1)Novartis, 2015 (US)chronic heart failure
N
NPh
Ph N
Me Me
O NHMs
O
selexipag (Uptravi®)J&J, Nippon Shinyaku, 2015 (US)pulmonary arterial hypertension
prostacyclin receptor agonist
Other Drugs
losartanARBs(1995)
dabigartanNOAC(2008)
captoprilACE inhibitors
(1981)
nifedipineCCBs(1975)
popranololβ-blockers
(1965)
chlorothiazidediuretic(1957)
warfarinanticoagulant
digoxincardiac gylcoside
(1954)
ticlopidineantiplatelet
(1978)
What’sNext?
Projected Rise in Deaths from Different Diseases
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