Introduction to Medicinal chemistry

Intended Learning Objectives

At the end of this lecture, the student will be able to:

• Explain various aspects of Medicinal chemistry

Contents

• Introduction to medicinal chemistry

• Various Aspects of medicinal chemistry

Medicinal chemistry

• Medicinal chemistry is a discipline at the intersection of chemistry and pharmacology that involves the identification, synthesis, and development of new chemical entities that are suitable for medical or pharmaceutical use.

• It is an interdisciplinary science combining variety of subjects such as organic chemistry, phytochemistry, pharmacology, toxicology, molecular biology, biochemistry, computational chemistry, physical chemistry, and statistics.

• It also includes the study of existing drugs, their pharmacological properties, toxic effects, and their quantitative structure-activity relationships (QSARs).

• Majority of the medicinal compounds, which are used as medicines are natural products and synthetic organic compounds.

• However, metal-containing compounds are also found to be useful as drugs.

– For example, cisplatin series of platinium-containing complexes are used as anticancer agents. These are as metal-based drugs.

Medicinal chemistry Objective

• The primary objective of medicinal chemistry is the design and discovery of new compounds that are suitable for use as drugs.

• Medicinal chemistry defined by IUPAC

“It concerns the discovery, the development, the identification and the interpretation of the mode of action of biologically active compounds at the molecular level”

• The discovery or design of a new drug not only requires a discovery process  but  also  the  synthesis of  the  drug,  a method of administration, the development of tests and procedures to establish how it operates in the body and a safety assessment.

• Drug discovery may also require fundamental research into the biological and chemical nature of the diseased state.

• These and other aspects of drug design and discovery require input from specialists in many other fields and so medicinal chemists need to have an outline knowledge of the relevant aspects of these fields.

Drug

• Drugs are strictly defined as chemical substances that are used to prevent or cure diseases in humans, animals and plants.

• A very broad definition of a drug would include “all chemicals other than food that affect living processes.”

• If the affect helps the body, the drug is a medicine.

• However, if a drug causes a harmful effect on the body, the drug is a poison.

• The same chemical can be a medicine and a poison depending on conditions of use and the person using it.

Pharmaceutical effect

• The activity of a drug is its pharmaceutical effect on the subject, for example, analgesic or b-blocker

• Its potency is the quantitative nature of that effect.

• Unfortunately the term drug is also used by the general public to describe the substances taken for their psychotic rather than medicinal effect

– However, these substances can also be used as drugs. E.g. Heroin, is a very effective painkiller used in terminal cancer cases.

Side effects

• Drugs act by interfering with biological processes, so no drug is completely safe.

• All drugs, including non-prescription drugs, act as poisons if taken in excess.

– E.g. overdoses of paracetamol can causes coma and death.

• All drugs have the potential for producing more than one response.

• In addition to their beneficial effects most drugs have non- beneficial biological effects.

– Aspirin, used to alleviate headaches, can also cause gastric irritation and occult bleeding in some people.

• The non-beneficial effects of some drugs, .eg. cocaine and heroin, are so undesirable that the use of these drugs has to be strictly controlled by legislation.

• Unwanted effects appearing at therapeutic doses are called side effects.

• However, side effects are not always non-beneficial;

– E.g. antihistamine- promethazine is licensed for the treatment of hay fever but also induces drowsiness, which may aid sleep.

• In contrast, adverse drug effects appearing at extreme drug doses are described as toxic effects.

Greeks used–pharmakon- for both poisons and medicinal products.

Drug resistance – Tachyphylaxis

• Drug resistance or tolerance occurs when a drug is no longer effective in controlling a medical condition.

– Acute, sudden decrease in response to a drug after its administration, i.e. a rapid and short-term onset of drug tolerance.

– It can occur after an initial dose or after a series of small doses

•   It arises in people for a variety of reasons.

– For example, the effectiveness of barbiturates often decreases with repeated use because the body develops mixed function oxidases in the liver that metabolize the drug, which reduces its effectiveness.

– The development of an enzyme that metabolizes the drug is a relatively common reason for drug resistance.

– Another general reason for drug resistance is the down regulation of receptors

– Downregulation occurs when repeated stimulation of a receptor results in the receptor being broken down. This results in the drug being less effective because there are fewer receptors available for it to act on.

• Drug resistance may also be due to the appearance of a significantly high proportion of drug-resistant strains of microorganisms.

Drug discovery – Stages

Medicinal chemistry covers the following stages:

 (i) The first stage new active substances or drugs are identified and prepared from natural sources, organic chemical reactions or biotechnological processes.

• They are known as lead molecules.

(ii) The second stageis optimization of lead structure to improve potency, selectivity and to reduce toxicity.

(iii) Third stageis development stage, which involves optimization of synthetic route for bulk production and modification of pharmacokinetic and pharmaceutical properties of active substance to render it clinically useful.

Need for Novel drugs

• New drugs are constantly required to combat drug resistance even though it can be minimized by the correct use of medicines by patients.

• They are also required for improving the treatment of existing diseases

• The treatment of newly identified diseases

• The production of safer drugs by the reduction or removal of adverse side effects.

Receptor

• A large number of drugs act through specific macromolecular components of the cell, which regulate critical functions like enzymatic activity, permeability, structural features, template function etc.

• These macromolecules, which bind and interact with the drugs, are called receptors.

• A  receptor  is  a  component  of  a  cell  or  organism  that interacts with a drug and initiates the chain of biochemical events leading to the drug’s observed effects.

Theory of receptors

• Theory of receptors has become one of the fundamental concepts of medicinal chemistry.

• Receptor sites -usually take the form of pockets, grooves or other cavities in the surface of certain proteins and glycoproteins in the living organism.

– They should not be confused with active sites- regions of enzymes where metabolic chemical reactions occur.

• Binding of a chemical agent - ligand- to a receptor sets in motion a series of biochemical events that result in a biological or physiological effect.

– Side effects arise when the drug binds to the receptor responsible for the desired biological response or to different receptors.

Pharmacophore

• The section of the structure of a ligand that binds to a receptor is known as its pharmacophore

• A part of a molecular structure that is responsible for a particular biological or pharmacological interaction that it undergoes

• IUPAC definition of a pharmacophore is: A pharmacophore is the ensemble of steric and electronic features that is necessary to ensure the optimal supramolecular interactions with a specific biological target structure and to trigger (or to block) its biological response

Agonist

Agonist—A  drug  that  activates  a  receptor  is  knows  as agonist, which has following properties;

– Agonists can differ in both affinity and efficacy for the receptor

– High efficacy agonists are full agonists because they elicit maximal effects

– Low efficacy agonists are partial agonists because they cannot elicit a maximal effect at receptors even at high concentrations

– Direct agonists act on receptors, while indirect agonists facilitate the actions of the endogenous agonist (the neurotransmitter, itself)

Antagonist

• Antagonist—A drug that does not activate the receptor is antagonist, which possess the following features;

– Antagonists also prevent the activation of the receptor by an agonist, thus antagonists are essentially zero efficacy drugs

– Competitive antagonists bind to the same binding site as the agonist and therefore compete with the agonist for that binding site

– Non-competitive antagonists have a different binding site to the agonist and therefore do not compete with the agonist.

Receptor site theory

• After attachment of drug molecule to a receptor site, a drug may either initiate a response or prevent a response from occurring.

– consider ‘lock-and-key’ principle for ligand–receptor interaction.

– Only keys (ligands) that fulfill all criteria for fitting into the lock (receptor) can open the door (produce an effect).

– Some keys can fit in the lock but not perfectly, consequently they cannot open the door, but they prevent the original key from fitting into the lock and opening the door.

– The concept of receptor antagonism is very often the underlying mechanism of drug action

– e.g. to prevent the constriction of airways in asthmatic conditions, receptor antagonists  are  administered-they  prevent  the  actions  of  the  signaling molecules causing muscle contraction (e.g. histamine antagonists)

One could regard an antagonist as an imperfect key and a receptor agonist as the perfect key.

Structure–activity relationship (SAR)

• Structure–activity relationship (SAR) is a method which consists of synthesizing and testing a series of structurally related compounds.

• It hence give the relation between the structure of the compound and its activity

• Quantitative measurements incorporated into structure– activity relationship determinations- QSAR

– e.g Successful use of QSAR -development of the antiulcer agents cimetidine and ranitidine in the 1970s

• Both SAR and QSAR are important parts of the foundations of medicinal chemistry.

Names of Drugs

• International Nonproprietary Names (INN)

Use of INN

• Nonproprietary names are intended for use in pharmacopoeias, labelling,  product  information, advertising and other promotional material, drug regulation and scientific literature, and as a basis for product names, e.g. for generics.

• National names – British Approved Names (BAN), Dénominations Communes Françaises (DCF), Japanese Adopted Names (JAN) and United States Adopted Names (USAN) are, with rare exceptions, identical to the INN.

Pharmacokinetic Parameters

Pharmacokinetics is the study of:

• Absorption

• Distribution

• Metabolism

• Elimination

Absorption

• Amount of drug that reaches the systemic circulation (bioavailability) is highly dependent on absorption

• Properties of the drug, route of administration and patient factors should be considered to ensure clinical effectiveness

• Most drugs are absorbed into the systemic circulation via passive diffusion

• Other mechanisms of absorption include: active transport, facilitated diffusion, pinocytosis/phagocytosis

• Absorption rate and amount depends on local blood flow at administration site (eg. sublingual vessels provide significant blood flow therefore rapid absorption)

Factors Affecting Absorption

• Molecular size:

– Small  size,  water  soluble  drugs  can  pass  through  channels  in membranes, large molecules cannot

• Local pH and drug ionization:

– Charged molecules do not cross membranes

• Total surface area for absorption:

– Small intestine has villi which increase the surface area for absorption, and hence is the primary site of absorption for most oral drugs

Distribution

• Process by which drugs are carried throughout the body to reach target sites of action

• Volume of Distribution (Vd)

• Actual volume of distribution (Vd): Anatomic volume that is accessible to drug, e.g. total body water - 40 L

Protein Binding

• Drug molecules in the blood are in two forms:

• Bound to plasma proteins – example, albumin, globulin

• Free form (unbound)

Principles of Protein Binding

• Free drug can distribute into tissues and exert its action, and is subject to metabolism and elimination

• Affinity of a protein binding site for a drug determines bound/unbound concentrations, and reversibility of interaction

• Saturation of binding sites may result in a large increase in unbound drug concentration, which could cause toxicity

• Decrease in albumin concentration (liver failure or nephrotic syndrome), can lead to toxicity of highly bound drug

• Competition for binding sites between drugs and endogenous substrates can result in interactions and toxicity

• Significant drug interactions can occur due to competitive protein binding

Metabolism

• Main site of biotransformation in the body is the ‘LIVER’

• Drug metabolizing enzyme pathways generally mediate 2 types of reactions:

• Phase I reactions (includes, oxidation, reduction and hydrolysis)

• Phase II reactions (includes, conjugation)

Elimination

• Different routes of elimination include:

• Stool (e.g. corticosteroids from biliary system)

• Kidneys (main site of drug elimination)

• Lungs (e.g. general anesthetics eliminated by expiration)

• Skin and mucous membranes (e.g. rifampin in tears)

“Kidneys” the Main Organ of Elimination

• Glomerular filtration

• Passive, pore size about 400-600 Angstroms

• Tubular secretion

• Active, against concentration gradient, saturable,

• Tubular reabsorption

• Can be active or passive (depending on charge)

Summary

• Medicinal chemistry is a discipline at the intersection of chemistry and pharmacology that involves the identification, synthesis, and development of new chemical entities that are suitable for medical or pharmaceutical use.

• Drugs are defined as chemical substances that are used to prevent or cure diseases in humans, animals and plants.

• The activity of a drug is its pharmaceutical effect on the subject

– For example, analgesic or antipyretic

• Its potency is the quantitative nature of that effect

• Unwanted effects appearing at therapeutic doses -side effects.

• The macromolecules, which bind and interact with the drugs, are called receptors

• The section of the structure of a ligand that binds to a receptor is known as its pharmacophore

• Agonist—A drug that activates a receptor is knows as agonist

• Antagonist—A drug that does not activate/or prevents the activation of the receptor is known as antagonist

• Structure–activity relationship (SAR) is a method which consists of synthesizing and testing a series of structurally related compounds.

– It hence give the relation between the structure of the compound and its activity

• Pharmacokinetics is the study of: Absorption, Distribution, Metabolism, and Elimination