DRUG DESIGNDr. Bilal Al-Jaidi

Introduction

Medicinal Chemistry is the science that deals with the design and developmnet of new pharmaceutical agents.

Medicinal Chemist interests in: The synthesis of drugs. The isolation of natural products. Establishing the structure activity

relationships of the compounds. Studying the drug-target interaction. The pharmacokinetic profile of drugs

Drug Discovery

Drug discovery is a costly and time consuming process… from 10000 obtained compounds, only one will reach the market.

After establishing the safety and efficacy of the designed compound on laboratory animals, clinical trials must be applied on human.

Clinical trials

Phase-I (lasts for 1 month -1 year): evaluate the safety, tolerability, pharmacokinetic and pharmacological activity of drugs on 20-100 volunteers.

Phase-II (lasts for 1-3 years): further assess the efficacy , safety of drugs in addition to dosing regimen in 300-600 patients.

Clinical trials

Phase-III (last for 2-6 years): covers several thousands of patients in clinics or hospitals; study the activity and possible side effects on the long term.

Phase-IV: it is the post marketing feedback, after prescribing drugs to the out patients.

Lead compound

Is a prototype compound that has many attractive properties, most importantly, good activity, stability and suitable pharmacokinetics.

Lead optimization is to modify the chemical structure of the lead compound in order to improve the desired properties and trying to minimize the unwanted ones.

Drug candidate and clinical drug

Drug candidate: is that drug obtained from the lead optimization experiment….needs extensive studies to be clinically available.

Clinical drug: compound that is ready for clinical trials.

Lead Discovery

Is the first step in drug discovery.

You can not discover a lead if you do not have: A well established bioassay…that will study

the efficacy and potency of compounds. High throughput screening and ultra high

throughput screening. Enzymatic assay. Instrumental analysis such as MS and NMR to

interpret the bioassay results.

Sources of the lead

1. If the biological target is known, then the lead compound will be the natural ligand of this receptor or enzyme

Adrenaline

HO

HO

NH2

OH

H

Noradrenaline

HO

HO

HN

OH

H

O

O

N

Acetylcholine

Lead for cholinergic agonistAnd antagonists

Leads for adrenergicAgonists and antagonists

Sources of the lead

2. The marketed drugs can be used as lead compounds.

3. Random screening: this approach is used if we do not know the biological target:

examples: the sulfa drug; sulfanilamide was used as the

lead for the development of many sulfa drugs. Aminoglycosides and tetracyclines were

discovered after random screening of soil samples on different bacterial strains

Sources of the lead

4. Non-random screening: in this approach the tested compounds having some structural similarity to a weakly active agents.

5. Drug metabolism studies:N

OHPh

Ph

OH

Terfinadine

N

OH

COOH

Ph

Ph

OH

Fexofinadinemore activeLess sedating antihistaminic agent

NN

OOH

Cl

NN

OOH

Cl

Hydroxyzine Cetirizine

O

Sources of the lead

6. From clinical observations: in this case the drug candidate exhibits more than one pharmacological action:

Examples: (Drugs off Label) Sildenafil was designed for anti-hypertensive

action but found to improve the erectile function. Buclizine and Meclizine first synthesized as anti-

allergic agents, but they exhibited a good activity in treating motion sickness.

Lead modification

The aim here is to improve the desired properties in the lead compound and try to reduce the toxic or un favorable effects.

The first step in this process is to identify the PHARMACOPHORE.

Pharmacophore is a collection of groups in the molecule that interact with the receptor or the enzyme and are responsible for activity

Pharmacophore and Auxophore

Auxophore: is the groups rather than the pharmacophore in the chemical structure.

Many roles have been identified for the auxophore: Hold the pharmacophoric groups in their

place. Interfere with the binding to the receptor…un-

favorable. Occupy an inert space. Affect the pharmacokinetic properties of the

whole structure.

Example of the study of pharmacophore

The pharmacophoric groups in opioid analgesics are shown below (Bold style):

the other groups (not in the bold style) are auxophoric group.

O

N

HO

OH

Morphine

O

N

HO

OH

Morphine

N

HO

OH

Levorphanol4X more potent as analgesicaddiction still possible

N

HO

PentazocineLower addiction liability

N

HO

Still an effective analgesic

the removal of the tetrahydrofuran ring did not affect the overall bioactive conformation of the compound

Lead modification

The second step in the lead modification is the functional group modification depending on the study of the pharmacophore.

Example: sulfonamide lead modification:SNH

O O

H2N

NH

O

CarbutamideHas antibacterial and hypoglycemic activity

SNH

O O

NH

O

TolbutamideHas only hypoglycemic activity (WHY??)

Lead modification

The second step in the lead modification is the functional group modification depending on the study of the pharmacophore.

Example: sulfonamide lead modification:SNH

O O

H2N

NH

O

CarbutamideHas antibacterial and hypoglycemic activity

SNH

O O

NH

O

TolbutamideHas only hypoglycemic activity (WHY??)

This is the antibacterialpharmacophore

This is the hypoglycemicpharmacophore

Lead modification

The third step is to construct the structure activity relationships.

Drugs can be classified into: Structurally specific: here the drug binds to

specific site (receptor, enzyme, DNA,…etc). Structurally non-specific: drug has no specific

site to bind with in order to exert its pharmacological effect (such as gaseous anesthetics, disinfectants and most of sedative hypnotics)

Structurally specific drugs are more potent than structurally non-specific ones

Structural modification

The main aim is to get more active, potent and safer agents compared to the lead compound.

Methods for structural modification: Homologation: is to lengthen the alkyl chain in

the chemical structure by CH2: Chain length up to 9 carbon atom….tolerable

(optimum lipophilicity and water solubility. Chain length more than 9 carbon atoms…low

water solubility… low availability.

OH

OH4-hexylresorcinoltopical anesthetic

Chain branching: alkyl branching will lower the lipophilicity. Alkyl branching will weaken the binding with the

biological target.

Ring chain transformation: Affects both lipophilicity and drug metabolism

NH2

PhenethylamineMAO substrate

NH2

AmphetaminePoor substrate for MAO

N

O

O

Arecoline

N

O

O

Acetylcholine

Bioisosterism: Bioisosteres are groups or substituents that have

chemical or physical similarities which produce similar biological activity.

Importance of the use of Bioisosteres:

Alter the pharmacokinetic properties. Attenuate toxicity. Modify activity. Potentiate activity.

Two types of Bioisosteres: Classical Bioisosteres. Non-classical Bioisosteres.

Classical Bioisosteres

Are atoms or molecules in which the peripheral layers of electrons can be considered identical.

Subclasses: Univalent: CH3 , NH2 , OH , F , Cl

Cl, SH Br, i-Pr I, t-Bu Divalent: -CH2- , -NH- , -O- , -S-

-CO-CH2- , -CO-NH- , -CO-O-, -CO-S-

Classical Bioisosteres

Trivalent: -CH= , -N= Tetravalent:

Ring equivalent:

C Si

C N

S

N

OHN S

Non-Classical Bioisostere

They do not have the same no. of atoms…this means that the size, shape and electronic properties are different…at the same time they have the same impact on biological activity.

Examples: OH

OS

OH

O OS

NH2

O O NO

OH

OH NHCN

X CF3 CN

NNO2

CH2 3

Structural modification to improve oral bioavailability

Factors affecting oral bioavailability:

Physicochemical stability. Biological stability:

Effect of intestinal enzymes. First pass metabolism.

Lipophilicity. Extent of ionization.

Lipophilicity

The orally administered drug must have moderate lipophilicity (logP = 2-5) in order to absorbed through the lipophilic mucus membrane.

It is recommended that one can predict the lipophilicity of the chemical compound before start synthesizing it.

P = [C]octanol /[C]water Octanol was selected because it simulates the

lipophilic membrane; lipophilic and sparingly soluble in water

Lipophilicity

Ionized drug will have lower lipophilicity than the neutral form.

is the degree of dissociation in water, depends on the ionization constant.

LogD: is the log of distribution coefficient that describe the lipophilicity of ionizable compound

Example of logD

LogD pH-1.31 2.00.12 7.51.73 10.0

ONH

OH

OMetaprolol

Prediction of lipophilicity

To predict the lipophilicity, we must know the lipophilicity of substituents.

Lipophilicity substituent constant (π)

Π = logPX –LogPH (Hansh approach)

Substituent or fragment constant

Example

Calculate the logP of Aspirin:

logP = 1.67-0.03-0.61-1.09+0.89 = 0.83

OH

O

O

O

Other factors affecting lipophilicity

Branching: logP will be lowered by 0.2 per branch.

Inductive effect of electron withdrawing groups.

Resonance effect: if it will affect the possibility of H-bonding.

Example

OHOH

Methanol Phenol

Methanol is more polar, less lipophilic than phenol

Effect of Ionization

Extent of ionization of drugs may affect the following:

Lipophilicity. Oral availability. Receptor-drug interaction. Excretion. Distribution

Effect of Ionization

At a given pH, there is an equilibrium between the ionized and unionized form.

Only the unionized form will be absorbed from the GIT.

The equilibrium between the ionized and unionized will be reestablished to generate unionized drug again for absorption (what are the factors affecting this equilibrium?)

Example

NNHO

PhenylbutazonepKa = 4.5Unionized in urinelow effect as uriccosuric agent

NNHO

SOO

pKa = 2.8better ionized in urinebetter action as uricosuric agent

Example

SNH

O O

H2N

NO S

N

O O

H2N

NO

unionizedimportant for getting into the bacterial cell

(important for pharmacokinetics)

Ionizedimportant for eznyme interaction

(important for pharmacodynamics)

Lipinski’s rule of five

The orally administered drug must not have: A molecular weight > 500 Dalton LogP > 5 H-bond donor > 5 H-bond acceptor > 10

There are some exceptions out of this rule: Drugs that have specific transporters such as

peptidomimetic agents. Drugs targeting CNS should have:

H-bond donor ≤ 3 H-bond acceptor ≤ 6

Veber findings

For better oral availability, drug candidate must have:

Rotatable bonds ≤ 10 Polar surface area ≤ 140 A°2

Total hydrogen bond count ≤ 12

Ajay findings

For drugs targeting CNS:

If the molecular weight, the degree of branching, the no. of rotatable bonds or the no. of H-bond acceptors increased, the compound will less likely to be CNS active.

If the aromatic density, no. of H-bond donors or logP is increased, the compound is more likely to be CNS active.

Some Exceptions

O

NHN

O

S

O

HO

H

NH2

cephalexin

O

NHNH

O

SH

OHO

H

NH2

D-Phe-Cys-Val

HNN

OO

NHN

OH2N

HNO

NH

N

O

O

NNH

O

NH2

TRH

Gln-His-Pro

NH

O

N

OHO

O O

Enalapril

NH

O

N

OHO

NH2O OH NH2

O

Phe-Ala-Pro

resembles resemblesresembles

This can be benefial

HN

N N

N

O

H2N

O OH

HN

N N

N

O

H2N

O O

O

NH2

AcyclovirValacyclovir

Valacyclovir will have better oral availability although it is more polar than acyclovir because it will absorbed by the peptide transporter from the intestine