Medicinal

Chemistry

1. IntroductionElin Julianti

Medicinal

Chemistry

Medicinal chemistry :

Field of pharmaceutical sciences which applies the principles of chemistry and biology to the creation of knowledge leading to the introduce of new therapeutic agents.

The medical chemist must not only be a competent organic chemist but must have a basic background in biological science, particularly biochemistry and pharmacology

Medicinal Chemistry:

Multi-dicipline Science

1.1 What is a drug?

• The medicinal chemist attempts to design and synthesize a pharmaceutical agent that has a desired biological effect on the human body or some other living system

• Active compound: a chemical compound able to trigger/induce/cause biological activities in living organism

• Biological activity: whole changes in a biological system triggered/induced/caused by a compound

• Drug : Any substance used in a pharmaceutical product that is intended to modify or explore physiological system or pathological states for benefit of the recipient (WHO).

1.1 What is a drug?

Medicinal

product

(65/65/EEC):

Any substance or combination of substances presented for treating or preventing disease in human beings or animals. Any substance or combination of substances which may be administered to human beings or animals with a view to making a medical diagnosis or to restoring, correcting or modifying physiological functions in human beings or in animals is likewise considered a medicinal product.

Pharmaceutical product: a dosage form containing one or more drugs along with other substances included during manufacturing process

• No drug is totally safe. Drugs vary in the side effects they might have

• The dose level of a compound determines whether it will act as a medicine or as a poison.

• The therapeutic index is a measure of a drug’s beneficial effect at a low dose versus its harmful effects at higher dose. A high therapeutic index indicates a large safety margin between beneficial and toxic doses.

• The principle of selective toxicity means that useful drugs show toxicity against foreign or abnormal cells but not against normal host cells

Application of drugs

• Provision of elements lacking in the organism: e.g.vitamins, mineral salt, hormones.

• Prevention of a disease or an infection: e.g. sera and vaccines

• Fight against an infection : e.g. chemoterapeutics,including antibiotics

• Temporary blocking of a normal function: e.g. general and local anesthetic and oral contraceptive.

• Correction of deranged function(a). Dysfunction, ex: cardiotonics for treatments of congestive heart

failure (b) hyperfunction, ex: metyldopa in arterial hypertension

• Detoxification of the body: e.g. antidotes

• Diagnostic auxiliary agents: e.g. radiopaque compounds

1.2. History

and

Development

• Treatment of diseases using

medicine: since pre-history

• First medicine: herbal medicine,

especially for treatment of

infectious diseases

• Chinese, Indian, Maya,

Mediterranean: Application of

herbal and mineral as medicines

since ancient centuries

1.2. History

and

Development

• Modern chemotherapy, Paul

Ehrlich (1854-1915): certain

chemicals showed selective

toxicity against certain microbes

(Arsphenamine)

• Lock and key theory, Emil

Fischer: rational explanation of

work mechanism of drug

• Further research: discovery of

antibiotics and sulfonamide

1.3

Drug

Target

• Pharmacodynamics is the study of how a drug binds to its target binding site and produces a pharmacological effect

• Drugs act on molecular targets located in the cell membraneof cells or within the cells themselves.

• Drug targets are macromolecules that have a binding site into which the drug fits and binds.

• Most drugs bind to their targets by means of intermolecular bonds.

• Electrostatic or ionic interactions, Hydrogen bonds, Van der Waals interactions, etc

Application

Dissolution of

Active Compound

Resorpstion

DistributionDeposition

Biotran

Excretion

Target

(Receptor)

Pharmacological

Effects

Clinical Effects Toxic Effects

Pharmaceutical

phase

Pharmacokinetic

phase

Pharmacodynamic

phase

1.4

Pharmacokinetic

Phase

The drug not only has to bind to its target, it has to reach it in the first place.

Processes involved:

• Absorption

• Distribution

• Metabolism

• Excretion

• Should be investigated during optimization of an active compound to be a drug candidate

Pharmacokinetics has sometimes beendescribed as ‘what the body does to the drug’ as opposed to pharmacodynamics—‘what the drug does to the body

Absorption

• Absorption/in take from surface of body (incl. gastrointestinal tract) to circulation system (lymph and blood)

• Absorption barrier: cell membrane (fluid mosaic model)

• Mechanisms: passive diffusion, facilitated diffusion, active transport, pinocytosis, phagocytosis

Passive

Diffusion

• Follow Fick‘s rule

• Diffusion rate of a substance:

• Proportional with concentration gradient, area of membrane, distribution koef., diffusion koef.

• Proportional with 1 / (thickness of membrane)

Facilitated

Diffusion

• Passive process, follows

conc. gradient

• Interaction with specific

protein

• Structure specific

• Saturation

Active

Transport

• Against conc. gradient, penetrates the membrane

• Energy needed: from ATP-cleavage

• Carrier protein

• Coupled with Na, substances and Na was transported in the same direction (complex formation of substance-Na-carrier protein

Pinocytosis,

Phagocytosis

• Pinocytosis: droplet of

small liquid

• Phagocytosis: small solid

particulate

• Both are vesicularly

absorbed

outer Membrane inner

A: Passive diffusion

B: Facilitated diffusion

C: Active transport

D: Phagocytosis

Distribusion

• Reversible transport of a substance in the body

• Influencing factors (from organism’s side): blood circulation in organ and tissue, permeability of membrane, pH difference (plasma and tissues)

• Influencing factors (from substance’s side): dimension of molecule, plasma and tissue protein binding, solubility and chemical properties

Metabolism

• Reactions occurred to a substance (drug) in the body, the products will be more polar and easier to be excreted.

• Main organ: liver (enzyme system: cytochrom P-450)

• Consist of phase 1 and 2

• Phase 1: oxidation, reduction, demethylation, deasetilation, etc.

• Phase 2: conjugation with sulphate, thiol, glucuronate etc.

Excretion

• Removal processes of a substance or its metabolite from the body

• Via different routes: kidney, fesses, sweat, inhalation

• Most of drugs: kidney as main organ

• Determines the half-life time of drug in the body

1.5. Classification of Drugs

• By pharmacological effect : analgesics, antipsychotics, antihypertensives, anti-asthmatics, and antibiotics

• By chemical structure : penicillins, barbiturates, opiates, steroids, and catecholamines

• By their effect on a target system : the cholinergic and the adrenergic drugs

• By their effect on a target structure : anticholinesterases

1.6 Naming of drugs and medicines

• Clinically useful drugs have a trade (or brand) name

Ex : Sildenafil ➔ Viagra®

Paclitaxel ➔Taxol®

• Most structures produced during the development of a new drug are not considered for the clinic. They are identified by simple codes that are specific to each research group

Ex : Ro31-8959, ABT-538, and MK-639

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