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