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