Congratulation and Congratulations and Welcome Welcome to the new year

Medicinal Chemistry 1 2010212

Dr. Nashwa Hafez Zaher

Aims

To provide An introduction on drug actions.

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

Objectives
At 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 drugreceptor 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.

Curriculum
Introduction 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. Mid Term examination : 30% MCQs, Fill in the Blank, Short answers. Assignments / projects : 10%

Final Examination : 50% 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.

What is Medicinal Chemistry?

It is the science dealing with drugs (Pharmacological action - mode of
action metabolism bioavailability - adverse reactions drug interactionsetc) .

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 drug what 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) 2) 3) 4) 5) 6)

Screening of natural materials. Medical folklore. Existing drugs. Serendipity. Screening synthetic bank. Natural neurotransmitters.

Structure Activity Relationship (SAR)

Is an approach attempts to identify the physicochemical properties of a drug and to see whether any of these properties has an effect on the drugs 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

Nalorphine

CH2-CH=CH2

Physicochemical properties
These 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. Oral Storage site

GIT
Circulation
Site of action

Parentral

Excretion

Metabolism

Routes of administration
1) Parentral:
I.V, intra arterial, intraspinal: No absorption barrier. 2) 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.

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.
affects

Changing substituents on a drug

significantly affects

Hydrophobic character

Biological activity.

Partition coefficient (p)

It is a measure of the drugs overall hydrophobicity. It can be measured experimentally by testing the drugs relative distribution in an noctanol/water mixture. The relative distribution is known as the Partition coefficient (p). It is obtained from the following equation:

Concentration of drug in octanol Concentration of drug in aqueos solution

Hydrophobic compounds have .....P value.

While hydrophilic compounds have a .P value.

may or may not

Varying substituents on the lead compound produce

Series of analogues having different hydrophobicities .

Affect biological activity.

Generally
Increasing hydrophobicity of a lead compound.
Results in

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

so

Increase in biological activity.

2- Electronic effects
The electronic effects of various substituents
affect

Drugs 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

+
Non-ionized form (Lipophilic) Ionized form (Hydrophilic)

neutral
amphoteric
ne utral ne utral
F O

acidic
COOH

basic
HN

we ak base

we ak base

What is the Predominate forms of ciprofloxacin at the different locations within the GIT?
O

O
COOH

O
COO

COO

N H2N

N H2N

N
HN

At stomach pH 1-3.5

At colon pH5.6-7

At duodenum pH 6-7

Degree of drug ionization

affects

Degree of drugs ionization

Depends on

Passage through membranes (ADE)

Acidic or basic strength

pKa is the expression for acid/base strength

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:

For acids:

For 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: 100 % Ionized = (pKa - pH) 1 + 10 For bases:
% Ionized = 100 1 + 10
(pH - pKa)

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

100 % Ionized = (3.5 1.5) 1 + 10

pKa asprin: 3.5

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:
O
H2 N COOH O O

Ibuprofen
S

Procainamide
O N

HN
O

NH

Phenytoin
O HN O HN

N Cl N

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

O O N N OH O N Cl

Cetirizine
Cl

Clemastine