Introduction to Medicinal Chemistry PDF

Module 1 INTRODUCTION TO MEDICINAL CHEMISTRY Presented by: Ricardo Jr. N. Arellano, RPh Q: The science which deals with the discovery and design of new and better therapeutic chemicals and development of these chemicals into new medicines and drugs (A) Combinatorial...

Module 1 INTRODUCTION TO MEDICINAL CHEMISTRY Presented by: Ricardo Jr. N. Arellano, RPh Q: The science which deals with the discovery and design of new and better therapeutic chemicals and development of these chemicals into new medicines and drugs (A) Combinatorial Chemistry (B) Synthetic Chemistry (C) Medicinal Chemistry (D) Pharmaceutical Chemistry  Introduction to Medicinal Chemistry MEDICINAL CHEMISTRY The primary objective of medicinal chemistry is the design and discovery of new compounds that are suitable for use as drugs.  Introduction to Medicinal Chemistry DRUGS - are low MW chemical substances that interact with macromolecular targets in the body to produce pharmacological effect  Introduction to Medicinal Chemistry 1. Pharmacodynamics Design a drug that will interact as powerfully and selectively as possible for the target → What the drug does to the body  Introduction to Medicinal Chemistry ENDOGENOUS COMPOUNDS >> body’s own natural chemicals EXOGENOUS COMPOUNDS >> foreign substances (XENOBIOTICS)  Introduction to Medicinal Chemistry 2. Pharmacokinetics Design the drug so that it is capable of reaching that target → What the body does to the drug  Introduction to Medicinal Chemistry 2. Pharmacokinetics A BSORPTION D ISTRIBUTION M ETABOLISM E XCRETION Introduction to Medicinal Chemistry PHARMACOKINETIC CONSIDERATIONS The rate-limiting/pre-requisite step for absorption of solid drugs (A) Disintegration (B) Dissolution (C) Distribution (D) Liberation  Introduction to Medicinal Chemistry DRUG ABSORPTION - Drug Dissolution (rate-limiting step) a. Particle size b. Particle surface area c. Solubility d. Ionization e. Polymorphism Prodrug approach I. Enhances the absorption of a drug that is poorly absorbed from the GI II. Alters biodistribution and half-life III.Masked the unpalatable taste of certain drugs (A) I and II (B) II and III (C) I and III (D) I, II and III  Introduction to Medicinal Chemistry DRUG DISTRIBUTION - ALBUMIN: most abundant protein in the plasma, can bind to large number of molecules 43. Remain in the systemic circulation and are not available to sites of biotransformation, receptors and excretion (A) Bound drugs (B) Unbound drugs (C) Free drugs (D) Both B and C  Introduction to Medicinal Chemistry PROTEIN BINDING - Bound-drugs a. remain in the systemic circulation b. not be available to sites of biotransformation, receptors and excretion. Drug-Albumin Complex acts as a RESERVOIR  Introduction to Medicinal Chemistry DRUG METABOLISM - All substances in the circulatory system, including drugs, metabolites, and nutrients, will pass through the liver. - Most molecules absorbed from the GIT enter the portal vein and are initially transported to the liver.  Introduction to Medicinal Chemistry First-Pass Effect - a significant proportion of a drug is metabolized by hepatic enzymes during the initial trip through the liver Example: LIDOCAINE – antiarrhythmic agent (60% is metabolized when given orally)  Introduction to Medicinal Chemistry Bioactivation 1. Azathioprine (immunosuppressant) → 6-mercaptopurine 2. Acyclovir (antiviral) → Acyclovir triphosphate Phase of metabolism that involves introduction functional groups or modification or unmasking of existing functionalities (A) Phase I Phase I aka FUNCTIONALIZATION (B) Phase II or NON-SYNTHETIC REACTIONS (C) Conjugation reactions (B), (C), (D) – (D) Synthetic reactions attachment of polar, endogenous compounds  Introduction to Medicinal Chemistry PHASES OF BIOTRANSFORMATION 1. Phase I (FUNCTIONALIZATION REACTIONS/Non-synthetic) - introduce functional groups or modify or unmask existing functionalities 2. Phase II (CONJUGATION REACTIONS/ Synthetic) - attach small, polar, and ionizable endogenous compounds to form water- soluble compounds  Introduction to Medicinal Chemistry DRUG EXCRETION KIDNEY: main route of excretion ENTEROHEPATIC RECIRCULATION: - drug reenters the intestinal tract from the liver through bile duct  Introduction to Medicinal Chemistry MEDICINAL CHEMISTRY - Studies how chemical structure influences biologic activity - Understand how these molecular and physicochemical properties influence the drug’s pharmacokinetics and pharmacodynamics Introduction to Medicinal Chemistry DRUG DISCOVERY AND DESIGN  Introduction to Medicinal Chemistry Paul Ehrlich and Sacachiro Hata produced arsphenamine (Salvarsan) for the treatment of syphilis.  Introduction to Medicinal Chemistry Structure-Activity Relationships (SARs) - relationship of how structural features of the molecule contribute to, or take away from, the desired biologic activity *Successful use of QSAR for Cimetidine and Ranitidine  Introduction to Medicinal Chemistry John Langley’s Theory of Receptors Receptor sites – pockets, grooves, cavities on surface of proteins Binding of Ligands (chemical agent) results in biological or physiological effect.  Introduction to Medicinal Chemistry BIOLOGIC TARGETS FOR DRUG ACTION - The relative “fit” is a function of physicochemical properties, in which the quality has a direct impact on biologic response. The birth of chemistry led to isolation and purification of ___ which are chemicals responsible for the biological effect of natural products (A) active principles (B) toxic compounds (C) phytotoxins (D) phytochemicals  Introduction to Medicinal Chemistry DRUG DISCOVERY AND DESIGN 1. Identification of new, previously undiscovered, biologically active compounds (HITS)  Introduction to Medicinal Chemistry DRUG DISCOVERY AND DESIGN 2. Chemical or functional group modification of a HIT to improve pharmacological, toxicological, physicochemical, pharmacokinetic properties → LEAD COMPOUND  Introduction to Medicinal Chemistry DRUG DISCOVERY AND DESIGN LEAD COMPOUNDS - with known chemical structure, MOA, functional groups responsible for the biologic activity (also called PHARMACOPHORES)  Introduction to Medicinal Chemistry DRUG DISCOVERY AND DESIGN 3. LEAD OPTIMIZATION – modification of functional groups of lead compound to improve its recognition, affinity and binding of pharmacophores for the targeted site  Introduction to Medicinal Chemistry REFINEMENT OF LEAD STRUCTURE 1. Determination of Pharmacophore 2. Alteration in Alkyl Chains (Length, branching, and rings) A. HOMOLOGATION - Chain lengthening B. BRANCHING  Introduction to Medicinal Chemistry REFINEMENT OF LEAD STRUCTURE 3. Functional Group Modification: BIOISOSTERISM - ISOSTERIC REPLACEMENT - the selection of structural components that make them interchangeable in drugs of the same pharmacological class  Introduction to Medicinal Chemistry DRUG DISCOVERY AND DESIGN 4. Rendering the lead compound into a DRUG CANDIDATE that is safe and suitable for use in human clinical trials, including preparation of a suitable DRUG FORMULATION. Introduction to Medicinal Chemistry HITS LEAD COMPOUNDS PHARMACOPORE LEAD OPTIMIZATION DRUG CANDIDATE  Introduction to Medicinal Chemistry DRUG DISCOVERY The most difficult aspect of drug discovery is that of LEAD DISCOVERY. Early discovery of useful drugs relied on (A) High-Throughput screening (B) Natural product screening (C) Random screening (D) Target-Dedicated Screening  Introduction to Medicinal Chemistry Discovery via Natural Product Screening – approach used in the late 19th century Ethnopharmacology – discipline of identifying potential natural product sources based on native lore  Introduction to Medicinal Chemistry Discovery via Random Screening of Synthetic Organic Compounds High-throughput Screening (HTS) – rapid large-scale screening/evaluation of molecules (LIBRARIES) - Structurally-related lead compounds are called ANALOGUES.  Introduction to Medicinal Chemistry Target Disease Plants Library ??? → hit X – lead compound X1 X2 X3 X4 X5 …. Analogue Xn Discovery of Penicillin by serendipity (1928) - Isolated and purified by Howard Florey and Ernst Chain (1939). - Using X-ray crystallography, Hodgkin elucidated the structure as a beta-lactam ring fused with thiazolidine ring. - Isolated and purified by Howard Florey and Ernst Chain (1939). - Using X-ray crystallography, Hodgkin elucidated the structure as a beta-lactam ring fused with thiazolidine ring.  Introduction to Medicinal Chemistry Discovery via Targeted Dedicated Screening and Rational Drug Design - more focused approach and uses greater knowledge (structural information) about the drug receptor (target) - involves molecular modeling and QSAR to better define physicochemical properties and pharmacophores  Introduction to Medicinal Chemistry Discovery via Drug Metabolism - metabolites of known drug are isolated and assayed for biologic activity First effective group of antibacterial drugs discovered (by chance) (A) Cephalosporins (B) Monobactams (C) Penicillins (D) Sulfonamides  Introduction to Medicinal Chemistry History Mietzch & Klarer synthesized azo dyes G. Domagk evaluated Prontosil rubrum (dye) → Inactive in vivo Trefouel & Bovet showed animal- treated urine was bioactive in vitro. p-aminobenzenesulfonamide (sulfanilamide) Foerster treated an infant suffering staphylococcal septicemia (puerpural sepsis). Bioreversible derivatives of drug molecules that undergo an enzymatic and/or chemical transformation in vivo to release the active parent drug, which can then exert the desired pharmacologic effect (A) Substrates (B) Metabolites (C) Prodrugs (D) Isomers  Introduction to Medicinal Chemistry Discovery via Observation of Side effects - Development of Phenothiazine antipsychotics Benzodioxanes (H-antagonist) 1. Diphenhydramine (antihistamine) 2. Ethelynediamine (sedative) Chlorpromazine (tranquilizer)  Introduction to Medicinal Chemistry Discovery via Observation of Side effects - Development of Phenothiazine antipsychotics Benzodioxanes (H-antagonist) 1. Diphenhydramine (antihistamine) 2. Ethelynediamine (sedative) Chlorpromazine (tranquilizer) Introduction to Medicinal Chemistry Introduction to Medicinal Chemistry  Module 1 INTRODUCTION TO MEDICINAL CHEMISTRY Presented by: Ricardo Jr. N. Arellano, RPh