lecture 12: medicinal chemistry - lcbim 12: medicinal chemistry . content ... library chemistry 3...
TRANSCRIPT
Lecture 12: Medicinal Chemistry
Content
• Organic Chemistry
• Isomers
• Functional Groups
• Steroids
• The drug discovery concept – general strategy
4th Century BC
Hippocrates: boiled willow bark to make tea…found that it
helped people with fevers
Later….scientists extracted
Yellow crystals from willow
bark
Called it Salicin after (Salix alba), genus species of willow
Found that this compond reduced fevers and inflamation
Side effects: stomach irritation and bad taste
Name this compound?
2-(acetyloxy)-benzoic acid
or
Acetylsalicylic acid
or
Aspirin
Organic Chemistry
- largest sub-discipline of chemistry is Organic Chemistry
-devoted to the study of carbon (C) based compounds
-How many compounds known?
-14 million known compounds
-12 million of them are organic
LSD THC
St. Johns Wort
Viagra
Caffeine
Aleve
Tryptophan apartame
Isomers: have the same chemical formula but different
molecular structure and PROPERTIES
C4H10
Isomers
Isomers: have the same chemical formula but different
molecular structure and PROPERTIES
C4H10
How many isomers does C5H12 have? Draw them.
Isomers
Functional Groups:
-impart characteristic physical and chemical properties
-In all drugs, it is these functional groups which gives the
chemical its physiological activity
Aspirin
Aspirin
1. Benzene ring
2. Carboxylic acid
3. Ester
1 allows the molecule to get
into your system
2 + 3 are the active drug
parts
Aspirin: How it works
Body: 2 types of communication
systems
1. nerves (breathing, reflex,
heartbeat)
2. chemicals (hormones): release
chemical into blood stream
(epinephrine, insulin etc)
Aspirin blocks cyclooxygenase
enzymes from producing
prostaglandins.
Prostaglandins produce fever and
swelling, increase sensitivity to pain,
inhibit vessel dilation
Drug Design
Goal:
1) to design/engineer a compound so that its beneficial
effects are enhanced while the side effects are
decreased.
willow bark tea--------------------------> aspirin
2) Relate chemical structure to drug activity
Two groups of drugs:
1. those that produce a physiological response (aspirin,
hormones, pyscho-active drugs)
2. inhibit the growth of substances that cause infection
(anti-biotics)
Ex. Morphine: highly addictive
Demerol: same active areas as morphine, not as addictive
Drugs
- All steroids have the same backbone structure
Drugs: Steroids
1930’s: in order to
study testosterone,
they had to process
one ton of bull
testicles to yield 5 mg
4 tons of pig ovaries
to yield 12 mg estone
Drugs: Birth Control
As with aspirin, birth control drugs came about through
molecular modifications.
The drug discovery concept –
general strategy
Target
Identification
HTS
Hit-to-Lead
(HtL)
New Lead
Optimisation
Projects (LO)
Candidate
Drug (CD)
Active-to-Hit
(AtH)
3 months to
2 years!
3-4 months
3 months
6-9 months
2 years
The Drug Discovery Process
Lead Compounds from a Variety of Sources
4. Natural Ligands
5. Existing Drugs
6. High Throughput Screening (HTS)
N
S
O
NHR
O
OOH
penicillins
O
OHOO
O
O
O
OOH
O
O
O
OH
NH
O
Htaxol
NH
N
NN
O
O
SN
O O
N
Viagra
1. Chance Discovery
2. Natural Products
3. Clinical Observation
Natural Ligands
OH
OH
OH
NH
RR=H adrenaline
R=Me noradrenaline
Catechol
bioisostere
(toxicity)
Increased size
(selectivity and duration)
Catechol
bioisostere
(toxicity)
Increased size
(selectivity and duration)
NH
OH
OH
NH
O
O
H
Formoterol
AstraZeneca
OH
OH
NH
OH
Salbutamol
GlaxoSmithKline
https://www.youtube.com/watch?v=m2GywoS77qc
https://www.youtube.com/watch?v=zw-iPofqj9o
N
O
O
NNH
O
O
Cialis
Eli Lilly
NH
NN
N
O
O
SN
O O
N
Levitra
Bayer
Existing Drugs
Also known as the “Me-Too” or “Me-Better” Approach
Issues: short duration
Multiple side effects and
incompatibility with other drugs
NH
N
NN
O
O
SN
O O
N
Viagra
Pfizer
Fewer side effects and
incompatibility with other drugs
36h duration (“the weekend pill”)
BEWARE: Patent Issues!!
High Throughput Screening (HTS)
• validated, tractable targets
• target selection for HTS
• industrialised process
• HTS assay technologies
and automation
• chemical diversity
• sample selection for HTS
How?
“An industrialised process which brings together validated,
tractable targets and chemical diversity to rapidly identify
novel lead compounds for early phase drug discovery”
50-70% of new drug projects originate from a HTS
Establishing a HTS
OH
N
Cl
O
O
chemical
space
compound
collection
compound
selection
human & pathogen
genomes
validated/
tractable
targets
target
ID
HT Screen
Development
Microtitre Plates – the HTS test tube
9mm
96 well
300-100ml
9mm pitch 384 well 25-5ml
4.5mm pitch
384 100-25ml
4.5mm pitch
1536 10-1ml
2.25mm pitch
For 200K data points:
125 x 1536 well plates
2000 x 96 well plates
500 x 384 well plates
Charnwood HTS Technologies; 1995-2001
3%
16%
2%4%
1%30%
1%
19%
24%
SPA
FLIPR
Filter
Fluorescence
Reporter
Yeast
TR-FRET
Alphascreen
FP
•Screening can utilise numerous
technologies e.g radioactivity,
fluorescence, luminescence
•None are universally applicable, each
with advantages and disadvantages
High throughput radioligand binding assays
Scintillation Proximity Assay – the first true homogeneous HTS screening technology
Nothing bound
bead not activated,
no light
Antibody/receptor
Molecule too far
away to activate
bead
Molecule cannot bind
Bound molecule
bead activated
light produced
I125
I125
Molecule binds
I125
I125
Suitable for I125, 3H, 33P
SPA (Scintillation Proximity Assay)
• First true homogeneous HTS technology
• Allows throughput of ~30K compounds/day in
384 format
• Easy to automate, no significant volume of
aqueous waste
BUT:
•Radioactive (safety headaches)
•Long read times (>30min/plate)
•Susceptible to quench artefacts
•Not applicable to all targets
FLIPR – a high throughput fluorimeter
Fluorescent Imaging Plate Reader
Real-time simultaneous imaging of 96- & 384-well plates
Used for HTS Ca2+ flux assays and ion channel screening
PC
Cooled CCD Camera
96/384-Tip Pipettor
Drawer Holding
5 Microplates
6 W Argon Ion Laser
• Cells loaded with fluorescent dye sensitive to Ca2+ (fluo-3)
• CCD camera images base of microtitre plate
• Addition of receptor agonist stimulates Ca2+ release, resulting in fluorescence increase
• Whole plate is read simultaneously, allowing kinetic analysis
• ‘Functional’ screen (i.e.whole cell) – greater relevance than simpler screening methods
• Throughput is 1000x greater than cuvette-based fluorimeter assay
FLIPR – how it works
Establishing a HTS
OH
N
Cl
O
O
chemical
space
compound
collection
compound
selection
human & pathogen
genomes
validated/
tractable
targets
target
ID
HT Screen
Development
Types of reactions
amide coupling
sulphonamide formation
reductive amination
Boronic acid coupling
Multicomponent reaction (3 variants so far)
Sulphonamide arylation
Ester hydrolysis
Acyl sulphonamide formation
Urea formation
Epoxide opening
Anhydride opening
Condensation to form benzamidazoles
Mitsunobu
N-, O- and S-Alkylation
Sulfonylurea formation
benzoxazinone formation
Pyridone formation
tetrazole formation
Boc or t-butyl deprotection
cyclization to heterocycles (21 types - see list)
Nucleophilic aromatic substitutions (2 types)
aminopyrazoles
imidazopyridines
imidazothiazoles
imidazopyrimidines
aminothiazoles
aminooxadiazoles
triazolopyrimidines
aminotriazoles
aminobenzimidazoles
triazolopyridines
pyrazolopyrimidine
3-aminoquinolines
triazolopyridazines
triazolopyrazines
thiazolidin-4-one
3-amino-1,2,4-triazoles
pyrimidin-2-ones
triazolo[1,5-c]quinazoline
imidazolidin-2-one
quinazolinone
1,2,4-oxadiazole
Library Chemistry
3 most commonly used reactions-
Amide coupling
Reductive amination
Sulphonamide formation
CCE – Common Combinatorial Reactions
• Amide Coupling
R3
OH
O
N
R2
HR1
N
R2
R1
R3
O
+
HATU, Et3N
NMP
• Sulphonamide Formation
N
R2
HR1
N
R2
SR1
R3
O O
SCl R
3
O O
+
Et3N
NMP
• Reductive Amination
N
R2
HR1
N
R2
R1
R3
H R3
O
+AcOH, NMP
Na(AcO)3BH
N N
NN
O
N
N+
PF6-
NO
HATU
NMP
Content
• Organic Chemistry
• Isomers
• Functional Groups
• Steroids
• The drug discovery concept – general strategy
Copyright material used: www.rsc.org/images/NTUlecture2; www.ebs.ogi.edu/~jnurmi/Chapt10%20Drugs