1- Introduction to Medicinal Chemistry Nashwa

Congratulationand

WelcomeCongratulations and

Welcome to the new year

Medicinal Chemistry 12010212

Dr. Nashwa Hafez Zaher

To provide An introduction on drug actions.

Aims

To gain knowledge about the chemistry and pharmacological activity of drugs acting on autonomic nervous system and cardiovascular system

ObjectivesAt the end of the course you should know how to: A. Define and identify the role of Medicinal Chemistry in the

process of Drug Discovery and Drug Development. B. Describe drug-target interactions including drug-receptor

and drug-enzyme interaction. C. Discuss the effect of different physicochemical properties

on biological activity. D. Discuss qualitative and quantitative structure-activity

relationships. E. Identify various Pharmacokinetic and Pharmacodynamic

properties of specific drug classes such as drugs acting on the autonomic nervous system, drugs acting on the cardiovascular system and diuretics.

CurriculumIntroduction to medicinal chemistry. Drug action on enzymes. Drug action on receptors. Drug development. Quantitative structure-activity relationship. Drugs acting on

Autonomic nervous system. Cardiovascular system (cardiotonics, antiarrhythmics, vasodilators, antihypertensive, antihyperlipedemic, drugs affecting blood and diuretics) Drug design for related drugs.

Evaluation Methods Quizzes : 10%

MCQs, True and false & Fill in the blank.

Final Examination : 50% MCQs, Fill in the Blank, Short answers.

Assignments / projects : 10%

Mid Term examination : 30%MCQs, Fill in the Blank, Short answers.

Reference books

1 -Medicinal Chemistry: An Introduction T.B., G. Thomas; Publisher; John Wiley & Sons Ltd.

Ed. 2nd 2007. 2 -Wilson and Gisvold's Textbook of Organic

Medicinal and Pharmaceutical Chemistry. John H. Block, John M. Beale, Jr. Publisher; Lippincott Williams and Wilkins, Ed. 12th 2010.

Text books

• 1- An Introduction to Medicinal Chemistry, Graham L. Patrick, Publisher; Oxford University Press Inc, New York, Ed. 4th 2009.

• 2- Principles of Medicinal Chemistry, T. L. Lemke, W.O. Foye, David A Williams, Victoria F Roche, S. William Zito, Wolters Kluwer, Publisher; Lippincott Williams and Wilkins, Ed. 6th 2008.

Introduction to medicinal chemistry

What is Medicinal Chemistry?

• It is the science dealing with drugs (Pharmacological action - mode of action – metabolism – bioavailability - adverse reactions – drug interactions-…etc) .

• It uses chemistry to study drugs with respect to pharmacokinetics and pharmacodynamics.

• Pharmacokinetics: Processes by which the drug passes during its way from the site of administration to the site of action.

• Pharmacodynamics: Drug-target interaction at the site of action.• Drug targets: Protein biomolecules such as receptors and enzymes at which drugs

bind .

• Its mission is to discover and develop new agents for treating diseases. In addition to studying the chemistry of receptors.

• Thus, medicinal chemistry occupies a strategic position at the interface of chemistry and pharmacology.

• Development of new pharmaceutical involves: chemistry, biochemistry, molecular biology, physiology, pharmacology, pharmaceutics and medicine.

Discovery of drugwhat are the characteristics that must be found in new drugs?

• More efficient.• Less toxic.• Minimal side effects.How can we improve the binding interaction of the

drug and its target?By studying the steric features of the drug. Improvement of its chemical stability and

pharmacokinetic properties.Studying quantitative structure activity relationship

QSAR of the designed new drug.

What are the sources of lead (prototype) compound?

1) Screening of natural materials.2) Medical folklore.3) Existing drugs.4) Serendipity.5) Screening synthetic bank.6) Natural neurotransmitters.

Structure Activity Relationship (SAR)Is an approach attempts to identify the physico-chemical properties of a drug

and to see whether any of these properties has an effect on the drug’s

biological activity.It will not be surprising then that a minor change in chemical structure, can lead to

dramatic switch in activity. In some examples the cause for this change in activity is attributed to some physical

factors such as polarity and its effect on passing the blood brain barrier (BBB),

rather than the ability or not of the drug to bind to its receptor.

A classical example is that of morphine and its derivatives.

Morphine Inactive

Heroin

CH2-CH=CH2

Nalorphine

Physicochemical propertiesThese properties have an important role in the

pharmacokinetics [ADME] or mechanism of action of the drug.

A drug can be superior to another just because it has good ADME, rather than good interaction with its target.

Circulation

Parentral

Site of action

Metabolism Excretion

Storage siteOral

GIT

Routes of administration2) GIT:

The drug must be dissoluted before absorption.This is affected by: i. pH of the GIT site from

which the drug is absorbed. Stomach: 1-3.5 colon: 5.6-7 Duodenum: 6-7 Lower ileum: 8

ii. Dissociation rate of the drug at that pH.

1) Parentral:

I.V, intra arterial, intra-spinal: No absorption barrier.

I.M, S.C, intra-dermal, intraperitoneal: Drug passes some membrane barriers till reaching circulation.

Drug Dissolution• It is the solubility of the drug in the fluids of the GIT.• What are the factors affecting dissolution of drug?1. Particle size: lower particle size increased surface

area exposed to fluids of GIT increased dissolution. e.g. Griseofulvin is formulated as micronized form to improve bioavailability.

2. pH of the medium: • Weakly acidic drugs dissolved in alkaline region of GIT.• Weakly basic drugs dissolved in acidic region of GIT.N.B. most drugs are absorbed from intestine than stomach

due to the large surface area of the intestine.

• Many physical, structural and chemical properties have been studied by SAR approach but the most common are:

1. Hydrophobicity.2. Electronic effect.3. Steric factors.

1 .Hydrophobicity • The hydrophobic character of a drug is vital to

how easily it crosses cell membranes and may also be important in receptor interactions.

• Changing substituents on a drug

significantly affects

• Hydrophobic character

affects

• Biological activity.

Partition coefficient (p)

• It is a measure of the drug’s overall hydrophobicity.

• It can be measured experimentally by testing the drug’s relative distribution in an n-octanol/water mixture.

• The relative distribution is known as the Partition coefficient (p).

• It is obtained from the following equation:

Hydrophobic compounds have .....P value.While hydrophilic compounds have a ….P value.

Concentration of drug in octanol

Concentration of drug in aqueos solution

P

• Varying substituents on the lead compound

produce

• Series of analogues having different hydrophobicities .

may or may not

• Affect biological activity.

Generally

Increasing hydrophobicity of a lead compound.

Crossing hydrophobic barriers such as cell membranes.Binding to target site ( enzyme or receptor).

Increase in biological activity.

Results in

so

2 -Electronic effects

The electronic effects of various substituents

affect Drug’s ionization or polarity.

affect

The easily passage through cell membranes. Or the strong interaction with the binding

site.

• Bronsted-Lowry Theory• An acid is any substance capable of yielding a proton

(H+).• A base is any substance capable of accepting a

proton.• A drug exist in equilibrium between the ionized

(more water soluble) and non-ionized (more lipophilic) forms.

• When acid loses its proton, it is referred to as having undergone dissociation.

COOH COO

+ H

Ionized form(Hydrophilic)

Non-ionized form (Lipophilic)

• Organic functional groups that cannot give up or accept a proton are considered to be neutral. e.g. alkyl alcohol, ether, ester amide,..

• A molecule that either can accept or yield a proton is amphoteric. e.g. ciprofloxacin.

N

O

N

F COOH

HN

acidicneutral

neutral

weak base

weak base

basic

What is the Predominate forms of ciprofloxacin at the different locations within

the GIT?

N

O

N

F COOH

H2N

N

O

N

F COO

H2N

N

O

N

F COO

HN

At stomachpH 1-3.5

At duodenumpH 6-7

At colonpH5.6-7

• The majority of drugs are either weak acids or weak bases.

• To reach their target, drugs have to cross biological membranes, which are lipophilic in nature. Therefore permits only unionized (lipophilic) form of drugs to pass through.

Degree of drug ionization

Degree of drugs’ ionization

Passage through membranes (ADE)

Acidic or basic strength

pKa is the expression for

acid/base strength

affectsDepends

on

Dissociation constant KH

• Is the relative proportion of the ionized and non-ionized forms of the drug found in equilibrium. i.e degree of ionization.

• e.g benzoic acid is a weak acid and only partially ionizes in water.

Degree of ionization dependent upon: • Dissociation constant of the chemical (pK) • pH of the environment, according to the Henderson-Hasselbalch

equation: For acids: pKa - pH = log [nonioinized] Acids: such as R-COOH,...

[ionized] For bases: pKa - pH = log [ionized] Bases: such as R-NH2,... [nonionized] Considering the ionization of two compounds:

Benzoic acid (weak acid; pKa = 4) Aniline (weak base; pK = 5)Weak acids and strong bases have high pKa values. Weak bases and strong acids have low pKa values.The majority of drugs are either weak acids or weak bases.

What is pKa and its importance?• pKa is the negative logarithm of the

dissociation constant “Ka”.• It is important in predicting the degree of

ionization of a drug at a given pH. How ?• For acids:

• For bases:

% Ionized = 100

1 + 10 (pKa - pH)

% Ionized = 100

1 + 10 (pH - pKa)

Q: At a pH of 1.5, what is the percent ionization of acetylsalicylic acid?

• pKa asprin: 3.5

% Ionized = 100

1 + 10 (3.5 – 1.5)

Q: At a pH of 7.9, what is the percent ionization of barbital of pKa 7.9?

• What is the most suitable location in the GIT (stomach or intestine) for absorption of the following drugs:

COOH

NHHN

O

O

H2N

O

O

N

Ibuprofen Procainamide

Phenytoin

N

S

NHN

HN

O

O

O

N

NO

Cl

Chlorpromazine

Diazepam Phenobarbital

• A truck driver complaining of seasonal allergies asks you to recommend an agent that will act as antihistamine but will not cause drowsiness. Choose between “Cetirizine” and “Clemastine”. If he takes a drug for indigestion which neutralizes stomach acid to pH 3.5 at the same time of taking antihistaminic

Cl

N

NO

OH

O

O N

Cl

Cetirizine Clemastine