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
Viagra
Aleve
Caffeine St. Johns Wort
THC
Tryptophan LSD
apartame
Isomers
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.
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)
Drugs
Ex. Morphine: highly addictive
Demerol: same active areas as morphine, not as addictive
Drugs: Steroids
- All steroids have the same backbone structure
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
The Drug Discovery Process
Target 3 months to
Identification 2 years!
HTS
3-4 months
Active-to-Hit
(AtH) 3 months
Hit-to-Lead
(HtL) 6-9 months
New Lead
Optimisation 2 years
Projects (LO)
Candidate
Drug (CD)
Lead Compounds from a Variety of Sources
R H
N
1. Chance Discovery O
S
penicillins
N
O
OH
O
2. Natural Products O
HN N
O O
N
N
S
N
Viagra
N
3. Clinical Observation O
O
4. Natural Ligands O
NH O O OH
O
5. Existing Drugs HO O
6. High Throughput Screening (HTS) OH H O
taxol O O
O
O
Natural Ligands
OH
HO
H
N R=H adrenaline
R
HO R=Me noradrenaline
https://www.youtube.com/watch?v=m2GywoS77qc
Formoterol Salbutamol
AstraZeneca GlaxoSmithKline
OH
H O H
OH N
H HO
HN N
HO
HO
O
Catechol Increased size
bioisostere (selectivity and duration)
(toxicity)
Catechol
bioisostere Increased size
(toxicity) (selectivity and duration)
https://www.youtube.com/watch?v=zw-iPofqj9o
Existing Drugs
Also known as the “Me-Too” or “Me-Better” Approach
Pfizer
O
Issues: short duration
HN N
O O
N Multiple side effects and
N
S
N Viagra incompatibility with other drugs
N
O
BEWARE: Patent Issues!!
Eli Lilly
O
N
Bayer N N Cialis
O H
O
O O HN
N
N
S
N
N
Levitra O
N O
O
36h duration (“the weekend pill”)
Fewer side effects and
incompatibility with other drugs
High Throughput Screening (HTS)
“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
How? • validated, tractable targets
• target selection for HTS
• industrialised process
• HTS assay technologies
and automation
• chemical diversity
• sample selection for HTS
Establishing a HTS
validated/
tractable
targets
HT Screen
target Development
ID
O
O
human & pathogen
genomes Cl
chemical OH
space compound
selection
compound
collection
Microtitre Plates – the HTS test tube
For 200K data points:
96 well 384
125 x 1536 well plates
300-100ml 100-25ml
9mm pitch 4.5mm pitch
384 well 1536
25-5ml 10-1ml
500 x 384 well plates
4.5mm pitch 2.25mm pitch
9mm
2000 x 96 well plates
Charnwood HTS Technologies; 1995-2001
SPA
FLIPR
Filter
30% 1% Fluorescence
4% Reporter
2% Yeast
TR-FRET
1% 16% Alphascreen
FP
•Screening can utilise numerous
19% 3%
technologies e.g radioactivity,
fluorescence, luminescence
24%
•None are universally applicable, each
with advantages and disadvantages
High throughput radioligand binding assays
Scintillation Proximity Assay – the first true homogeneous HTS screening technology
Molecule too far
away to activate
bead
Bound molecule I125
Nothing bound
bead activated Molecule binds
bead not activated, I125
no light light produced
Antibody/receptor
I125
Molecule cannot bind
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
FLIPR – how it works
PC 96/384-Tip Pipettor
• Cells loaded with fluorescent
dye sensitive to Ca2+ (fluo-3)
• CCD camera images base of
Drawer Holding
5 Microplates microtitre plate
• Addition of receptor agonist
6 W Argon Ion Laser stimulates Ca2+ release,
Cooled CCD Camera 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
Establishing a HTS
validated/
tractable
targets
HT Screen
target Development
ID
O
O
human & pathogen
genomes Cl
chemical OH
space compound
selection
compound
collection
Library Chemistry
Types of reactions
amide coupling
sulphonamide formation 3 most commonly used reactions-
reductive amination aminopyrazoles
Boronic acid coupling
Amide coupling
Multicomponent reaction (3 variants so far)
imidazopyridines
imidazothiazoles
Sulphonamide arylation imidazopyrimidines
Ester hydrolysis
Reductive amination aminothiazoles
Acyl sulphonamide formation aminooxadiazoles
Urea formation
Sulphonamide formation triazolopyrimidines
Epoxide opening aminotriazoles
Anhydride opening aminobenzimidazoles
Condensation to form benzamidazoles triazolopyridines
Mitsunobu pyrazolopyrimidine
3-aminoquinolines
N-, O- and S-Alkylation
triazolopyridazines
Sulfonylurea formation
triazolopyrazines
benzoxazinone formation
thiazolidin-4-one
Pyridone formation
3-amino-1,2,4-triazoles
tetrazole formation
pyrimidin-2-ones
Boc or t-butyl deprotection
triazolo[1,5-c]quinazoline
cyclization to heterocycles (21 types - see list)
imidazolidin-2-one
Nucleophilic aromatic substitutions (2 types)
quinazolinone
1,2,4-oxadiazole
CCE – Common Combinatorial Reactions
• Amide Coupling
O N PF6 -
1 O HATU, Et3N 1 N
R H R 3
N N R N N +
2
+ HO R
3
2 O
N
R NMP R
HATU N
• Sulphonamide Formation
Et3N O O
1 O O 1
NMP
R H R S 3 N
N S N R
2
+ Cl R
3
2
O
R NMP R
• Reductive Amination
O Na(AcO)3BH
1 1
R H R 3
N 3 N R
2
+ H R
2
R AcOH, NMP R
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
