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PHARMACEUTICAL AND MEDICINAL ORGANIC CHEMISTRY LANZON, KAR  HISTORY OF MEDICINAL CHEMISTRY KAR Lanzon, RPh  History Healers were priest-magician or priest-physician spiritual incantations, application of noxiou...

PHARMACEUTICAL AND MEDICINAL ORGANIC CHEMISTRY LANZON, KAR  HISTORY OF MEDICINAL CHEMISTRY KAR Lanzon, RPh  History Healers were priest-magician or priest-physician spiritual incantations, application of noxious and harmful materials, and administration of herbs and plants KAR Lanzon, RPh  History: Drugs of Antiquity Egyptians - embalming - Ebers papyrus - discovered by George Ebers - “medico-medical” - e.g., acacia, castor bean, fennel KAR Lanzon, RPh  History: Drugs of Antiquity Chinese - Emperor Shen Nung - Pen T’Sao – Chinese pharmacopeia - ch'ang shang – antimalarial alkaloid - ma huang commercial sources: Ephedra sinica, Ephedra equisetina KAR Lanzon, RPh  History: Drugs of Antiquity American Indians - chaulmoogra fruit Commercial sources: Hydnocarpus wightiana Hydnocarpus kurzii KAR Lanzon, RPh  History: Drugs of Antiquity South American Indians - cocaine (Erythroxylum coca) - used mushrooms as hallucinogens Brazil - emetine – ipecac root (Cephaelis ipecacuanha) - still used for the treatment of amebiasis or amoebic dysentery KAR Lanzon, RPh  History: Drugs of Antiquity Greeks - Dioscorides – wrote De Materia Medica or the Medicinal Material - some drugs described: aloe, belladonna, colchicum, ergot, hyoscyamus, and opium KAR Lanzon, RPh  History: Middle Ages Philippus Aureolus Theophrastus Bombastus von Hohenheim - “In all things there is a poison, and there is nothing without a poison. It depends only upon the dose whether a poison is a poison or not…” - mercury, lead, arsenic, antimony KAR Lanzon, RPh  History: 17th to 20th Century - from natural sources: - Carl Wilhelm Scheele - discovered the following chemicals: lactic acid, citric acid and tartaric acid - Friedrich Sertürner - isolated morphine from opium (Papaver somniferum) KAR Lanzon, RPh  History: 17th to 20th Century - Pierre-Joseph Pelletier - isolated emetine from ipecacuanha - purification of caffeine, quinine and colchicine - increased use of “pure” substances as therapeutic agents KAR Lanzon, RPh  History: 17th to 20th Century - William Withering - used digitalis for the treatment of edema and heart conditions (Digitalis purpurea) - Albert Niemann - isolation of cocaine KAR Lanzon, RPh  History: 17th to 20th Century - synthetic derivative: - Paul Ehrlich - produced compound 606 / arsphenamine / Salvarsan® - antisyphilis “magic bullet” - proposed selective toxicity - used until 1940s when it was replaced by penicillins - Father of Chemotherapy KAR Lanzon, RPh  History: 17th to 20th Century Gerhard Domagk - 2,4-Diaminoazobenzene-4'-sulfonamide (Prontosil) – a red dye that can cure systemic gram-positive bacterial infections D.D. Woods and Paul Fildes - observed the antagonistic action between sulfonamide-like drugs/sulfonamides and p-aminobenzoic acid KAR Lanzon, RPh  History: 17th to 20th Century Alexander Fleming - discovery of penicillin (Penicillium notatum) Howard Florey and Ernst Chain - further examined and produced a pure form of penicillin KAR Lanzon, RPh  DEVELOPMENTS: Psychopharmacologic Agents Chlorpromazine (Thorazine®) - Paul Charpentier – first synthesized the molecule - Simone Courvoisier – observed distinctive effects on animal behavior - Henri Laborit – noticed distinctive psychotropic effects in man - Pierre Deniker and Jean Delay – published a clinical trial treatment in psychotic patients - released in the market by Rhône-Poulenc (Largactil®) KAR Lanzon, RPh  DEVELOPMENTS: Psychopharmacologic Agents Anxiolytics - BENZODIAZEPINES - Meprobamate (Miltown®) - Frank M. Berger – accidental discovery - mephenesin KAR Lanzon, RPh  DEVELOPMENTS: Psychopharmacologic Agents Anxiolytics - BENZODIAZEPINES - Chlordiazepoxide (Librium®) - Lowell Randall – tested the crystallized compound synthesized by Leo Sternback KAR Lanzon, RPh  DEVELOPMENTS: Endocrine Therapy INSULIN - Frederick Banting and Charles Best – isolated it from a dog's pancreas - together with James Collip and John McLeod, they produced a pure form from the pancreases of cattle - Eli Lilly’s Humulin® - first synthetic human insulin to be sold in the market and approved by USFDA KAR Lanzon, RPh  DEVELOPMENTS: Local Anesthetics COCAINE (Erythroxylon coca) – naturally- occurring alkaloid - Albert Niemann - isolated cocaine from the plant - Richard Willstatter - determined the structure of cocaine - Carl Koller or “Coca Koller” – cocaine numbed the tongue, realizing that it's an effective, non-irritating anesthetic for the eye KAR Lanzon, RPh  DEVELOPMENTS: Local Anesthetics benzocaine, procaine, tetracaine, lidocaine - structural analogs of cocaine KAR Lanzon, RPh  DEVELOPMENTS: Anticancer Agents 6-MERCAPTOPURINE (Purinethol®) - George Hitchings and Gertrude Elion - Hitchings – it is possible to use an antagonist to stop bacterial or tumor cell growth by interfering with nucleic acid synthesis KAR Lanzon, RPh  DEVELOPMENTS: Anticancer Agents CISPLATIN – inorganic molecule with simple structure - second-generation compounds such as carboplatin KAR Lanzon, RPh  PHARMACEUTICAL AND MEDICINAL ORGANIC CHEMISTRY LANZON, KAR  MEDICINAL CHEMISTRY is a science which incorporates different branches of chemistry and biology in the research for the discovery and design of new and better therapeutic chemicals and development of these chemicals into new medicines and drugs. KAR Lanzon, RPh  Roles of a Medicinal Chemist 1. Make new compounds 2. Determine the effect of the drug on biological processes 3. Alter the structure of the compound for optimum effect and minimum side effects 4. Study uptake, distribution, metabolism, and excretion of drugs. KAR Lanzon, RPh  REVIEW OF FUNCTIONAL GROUPS KAR Lanzon, RPh  FUNCTIONAL GROUPS - a group of atoms responsible for the characteristic reactions of a particular compound KAR Lanzon, RPh FUNCTIONAL GROUPS KAR Lanzon, RPh ACIDIC functional groups KAR Lanzon, RPh  ACIDIC functional groups ▪ The tetrazole ring provides the best charge delocalization since resonance allows the charge to be equally shared among all five atoms in the ring. KAR Lanzon, RPh  ACIDIC functional groups ▪ hydrophilic ▪ can form salts when combined with bases ▪ Carboxylic acids ▪ esterified for the purpose of prodrug formation ▪ undergo acid- or enzyme-catalyzed decarboxylation reactions KAR Lanzon, RPh  BASIC functional groups Types: a. Aliphatic and alicyclic amines the most common basic functional groups KAR Lanzon, RPh  BASIC functional groups Types: b. Aromatic Amines i.e., procainamide are much less basic and for all intents and purposes can be considered neutral KAR Lanzon, RPh  BASIC functional groups Types: c. Aromatic, heterocyclic nitrogens i.e., vary in their basicity, but in general are much less basic than aliphatic & alicyclic amines KAR Lanzon, RPh  BASIC functional groups Types: d. Additional basic functional groups imines hydrazines amidines KAR Lanzon, RPh  NEUTRAL functional groups ▪ those that are incapable of ionization ▪ can enhance either solubility depending on their ability to form hydrogen bonds with water ▪ Hydrogen bonding ▪ primary mechanism for increasing the water solubility of non-electrolytes KAR Lanzon, RPh  Acid & Base: Major Physicochemical Properties pKa and Ionization Lipophilicity-Hydrophilicity Salt formation KAR Lanzon, RPh  Estimation of the Relative Acid-Base Strength The ionization constant (Ka) indicates the relative strength of the acid or base. An acid with a Ka of 1x10-3 is a stronger acid than one with a ka of 1x10-5 A base with a Ka of 1x10-7 is weaker than one with a ka of 1x10-9 KAR Lanzon, RPh  Estimation of the Relative Acid-Base Strength The negative log of the ionization constant (pKa) also indicates the relative strength of the acid or base. An acid with a pKa of 5 (Ka=1x10-5) is weaker than one with pKa of 3 A base with a pKa of 9 is stronger than one with a pKa of 7 KAR Lanzon, RPh  Acidic-Basic: Salt Formation Salt is the combination of an acid and a base. All salts are strong electrolytes (with few a exceptions: mercuric and cadmium halides and lead acetate) The salt form of the drug is more soluble than its parent molecule. KAR Lanzon, RPh  Acidic-Basic: Salt Formation Drug salts can be divided into two classes: 1) Inorganic salts: are made by combining drug molecules with inorganic acids and bases, such HCl, H2SO4, KOH, and NaOH. 2)Organic salts: are made by combining two drug molecules, one acidic and one basic. KAR Lanzon, RPh Acidic-Basic: Salt Formation KAR Lanzon, RPh Acidic-Basic: Salt Formation KAR Lanzon, RPh  Acidic-Basic: Salt Formation Sodium salt formation from carboxylic acid: RCOOH NaOH RCOO-Na+ H 2O + + R3NH+Cl- R3N + HCl Hydrochloric salt formation from an aliphatic amine KAR Lanzon, RPh  Acidic-Basic: Drug Distribution and pKa Drugs in their unionized forms will tend to distribute throughout the body more rapidly than will ionized molecules. In general, drugs pass through the nonpolar membranes of capillary walls, cell membranes, and the blood-brain barrier in the unionized form. KAR Lanzon, RPh KAR Lanzon, RPh KAR Lanzon, RPh KAR Lanzon, RPh KAR Lanzon, RPh KAR Lanzon, RPh KAR Lanzon, RPh KAR Lanzon, RPh KAR Lanzon, RPh KAR Lanzon, RPh  PHARMACEUTICAL AND MEDICINAL ORGANIC CHEMISTRY KARLanzon  Unit Outline Definition and Classification of Drugs Drug Discovery Process Drug-Receptor Interaction Drug Target KAR Lanzon, RPh  DRUG - any substance intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease, or to affect or alter the structure or function of the body of man or other animals KAR Lanzon, RPh  DRUG: CLASSIFICATIONS 1. Origin 2. Medicinal use 3. Type of diseases treated KAR Lanzon, RPh  Classification according to ORIGIN Natural compounds: materials obtained from both plant and animal Synthetic compounds: either pure synthesis or synthesis of naturally occurring compounds to reduce their cost Semi-synthetic compounds: the natural intermediate of some drugs could be used for the synthesis of a desired product KAR Lanzon, RPh Classification according to ORIGIN KAR Lanzon, RPh  Classification according to MEDICINAL USE I. Chemotherapeutic agents: Drugs which are used to fight malignant cells/tissues II. Pharmacodynamic agents: Drugs that act on the various physiological functions of the body KAR Lanzon, RPh  Classification according to TYPE OF DISEASES TREATED 1. Infectious diseases: person to person by outside agents, bacteria, viruses, fungi, or parasites 2. Non-infectious diseases: disorders of the human body caused by genetic malfunction, environmental factors, stress, or old age 3. Non-diseases: alleviation of pain, prevention of pregnancy, anesthesia KAR Lanzon, RPh  Definition of Terms Ligand - chemical agent that binds to the receptor Receptor - where the ligand binds Pharmacophore - the section of the structure of the ligand that binds to a receptor KAR Lanzon, RPh  Definition of Terms Structure-Activity Relationship - exhibited by compounds with similar structures to a pharmacologically active drug Lead Compounds - compounds on which the development is based Analogues - synthetic compounds developed from a lead compound KAR Lanzon, RPh KAR Lanzon, RPh Definition of Terms KAR Lanzon, RPh Definition of Terms KAR Lanzon, RPh  Hallmark Sources of Drugs and Lead Compounds PLANTS: Atropa belladonna Papaver somniferum Digitalis purpurea, Digitalis lanata Cinchona succirubra Pilocarpus jaborandi Taxus brevifolia Catharanthus roseus Artemisia annua KAR Lanzon, RPh  Hallmark Sources of Drugs and Lead Compounds ANIMALS Insulin - extracted by Banting and Best from dog pancreas - synthesized by the β-cell of the Islets of Langerhans in pancreas - commercial sources of insulin: - porcine and bovine pancreatic tissue - insertion of genes into special E. coli bacteria to produce a synthetic insulin KAR Lanzon, RPh  Hallmark Sources of Drugs and Lead Compounds MICROORGANISMS Penicillium notatum Cephalosporium acremonium Streptomyces cattleya Bacillus polymyxa Streptococcus orientalis Bacillus subtilis Streptomyces aureofaciens Streptomyces venezuelae KAR Lanzon, RPh  Drug Discovery and Drug Development Why is there a need for new drug designs and continuous discovery of new compounds? - to combat drug resistance, tolerance, or tachyphylaxis - improve treatment of existing diseases - for treatment of newly identified diseases - production of safer drugs by reduction or removal of adverse effects KAR Lanzon, RPh  DRUG DISCOVERY: Natural Product Screening ”Leads” and plant sources from folklore medicine were assayed for their many types of pharmacologic actions. KAR Lanzon, RPh  DRUG DISCOVERY: Random Screening all synthetic organic compounds available are tested in pharmacologic assays = for a specific type of biological activity High-throughput Screening – large-scale and computer-controlled – compounds are tested in a variety of bioassays KAR Lanzon, RPh KAR Lanzon, RPh  DRUG DISCOVERY: Rational Drug Design focused approach on structural knowledge of the receptors or ligands to design, identify, or create a “lead” involves molecular modeling and QSARs (Quantitative Structure-Activity Relationship) – physicochemical properties – pharmacophoric groups essential in biological activity KAR Lanzon, RPh  DRUG DISCOVERY: Rational Drug Design KAR Lanzon, RPh  DRUG DISCOVERY: Drug Metabolism Studies for clinical candidates or already in the market metabolites are isolated and assayed for biological activity (advantage) KAR Lanzon, RPh ❖ Early drug design started with the elucidation of the structure of the natural product, followed by selective changes in the molecule. The latter is done for: 1. the reduction of an undesirable pharmacologic response; 2. obtaining a better pharmacokinetic response; 3. altering the drug’s metabolism; 4. securing a more plentiful, less costly supply; and producing a competing product. KAR Lanzon, RPh  DDD PROCESS Discovery Lead optimization Toxicology and Clinical Development KAR Lanzon, RPh  DDD PROCESS Discovery Identification of NEW, or PREVIOUSLY UNDISCOVERED Biologically active compounds “HITS” KAR Lanzon, RPh  DDD PROCESS Lead optimization Converting these “hits” to “LEAD” COMPOUNDS aka PROTOTYPE by the modification of functional groups KAR Lanzon, RPh  What kind of compounds become drugs? Lipinski rule of 5 = Pfizer rule of 5 = rule of 5 Aka rule of drugability or drug likeliness ○ Not more than 5 hydrogen bond donors ○ Not more than 10 hydrogen bond acceptors ○ A molecular weight under 500g/mol ○ A partition coefficient log P less than 5 ○ Number of rotatable bonds not less than 10 KAR Lanzon, RPh  Revised RO5 (2002) 1. The substance should have a molecular weight of 500 or less. 2. It should have fewer than five hydrogen-bond donating functions. 3. It should have fewer than ten hydrogen-bond accepting functions. 4. The substance should have a calculated log P (c Log P) between approximately −1 to +5. KAR Lanzon, RPh  DDD PROCESS Lead optimization change in chain length and branching of an alkyl chain alters its lipophilic character and therefore its pharmacokinetic properties KAR Lanzon, RPh  DDD PROCESS Toxicology and Clinical Development Render it a DRUG CANDIDATE for clinical trial (4) KAR Lanzon, RPh Overview of DDD process KAR Lanzon, RPh Drug-Receptor Interaction KAR Lanzon, RPh  Drug-Receptor Theories The drug must bind to the receptor/enzyme/target in order to elicit an effect. Only one ligand can bind to the binding site of the receptor/enzyme/target. It is derived from and obeys the Law of Mass Action KAR Lanzon, RPh  Drug-Receptor Theories Different interactions/bonds are involved in the drug-receptor complex formation Most drug-receptor interactions are made via weak chemical bonds and are therefore reversible KAR Lanzon, RPh  Drug-Receptor Theories Irreversible drug-receptor interactions are not common and only occur via covalent bonds usually undesirable interventions are required to reverse the effects may sometimes be caused by carcinogenicity or mutagenicity KAR Lanzon, RPh  LOCK-AND-KEY the substrate is completely complementary in shape to the active site, so that it fits in ‘perfectly’ KAR Lanzon, RPh  INDUCED FIT the substrate and active site are not completely complementary, but there is still some complementarity KAR Lanzon, RPh  Drug-Receptor Theories Hypothesis of Clark: pharmacologic effect of the drug depends on the percentage of the receptors occupied response is proportional to the number of occupied receptors maximum pharmacologic effect can be obtained if all the receptors are occupied KAR Lanzon, RPh  Drug-Receptor Theories Hypothesis of Ariens and Stephenson: effectiveness of a drug lasts as long as the receptor is occupied affinity KAR Lanzon, RPh  Drug-Receptor Theories Hypothesis of Paton: effectiveness of a drug does not depend on the actual occupation of the receptor but by obtaining proper stimulus response is proportional to the rate of drug- receptor complex formation intrinsic activity KAR Lanzon, RPh  Determinants of Drug Action 1) STRUCTURAL DETERMINANTS 2) PHYSICOCHEMICAL DETERMINANTS KAR Lanzon, RPh  Relationship of Structure to Biologic activity Crum-Brown & Fraser – many compounds containing 3˚ amine groups contained muscle relaxant activity – disproven by Loewi and Navrati Specific chemical groups or nuclei were responsible for specific biologic effect KAR Lanzon, RPh KAR Lanzon, RPh  Selectivity of Drug Actions and Drug Receptors Paul Ehrlich - developed the concept of drug receptors receptor hypothesis that “side chains” on the surfaces of the cells were “complementary” to the dyes KAR Lanzon, RPh  Selectivity of Drug Actions and Drug Receptors interaction in antimicrobial is toxic selectivity of drug action through the “magic bullet” permitted eradication of disease states without significant harm to the organism selective toxicity KAR Lanzon, RPh  Selectivity of Drug Actions and Drug Receptors Ing - explained the hypothesis that one chemical group can produce two different biologic effects (muscle relaxation and contraction) tubocurarine and acetylcholine = antagonism KAR Lanzon, RPh Selectivity of Drug Actions and Drug Receptors KAR Lanzon, RPh  Selectivity of Drug Actions and Drug Receptors The explanation provides support to the concept that structure of a molecule, composition and arrangement of functional groups determine the type of pharmacologic effect that it possesses requirements: -quaternary ammonium or protonated tertiary ammonium acting on cholinergic NS -larger molecule than acetylcholine KAR Lanzon, RPh  Selectivity of Drug Actions and Drug Receptors Woods-Fildes (antagonism and selectivity) sulfanilamide and p-aminobenzoic acid (PABA) both contains acidic functional groups and have almost the same steric and electronic properties KAR Lanzon, RPh KAR Lanzon, RPh  Biologic Targets for Drug Action drug + biologic target (receptor, enzyme, nucleic acid) = pharmacologic activity relative “fit” is based on the physicochemical properties of the functional groups The quality of “fit” has a direct impact on the biologic response produced KAR Lanzon, RPh  Biologic Targets for Drug Action Baker – active-site-directed irreversible inhibition – covalent bond formation between receptor and ligand KAR Lanzon, RPh  STEREOCHEMISTRY AND DRUG ACTION Approx. one in every four drugs in the market is some type of isomeric mixtures majority are racemic mixtures; “racemates” – but it can lead to: -toxicity/adverse effects -active/inactive form -diff. in absorption - diff. in biologic activity KAR Lanzon, RPh STEREOCHEMISTRY AND DRUG ACTION KAR Lanzon, RPh  STEREOCHEMISTRY AND BIOLOGIC ACTIVITY EASSON-STEDMAN HYPOTHESIS – selective reactivity of one enantiomer with its receptor – the more potent enantiomer should be involved in a three- point fit to the receptor KAR Lanzon, RPh  PEPTIDE AND PROTEIN DRUGS made up of amino acids linked by amide/peptide bonds peptide = 15 to 50 aa protein = more than 50 aa aa - common backbone - basic amine attached to alpha-carbon of carboxylic acid + different side chains KAR Lanzon, RPh  PEPTIDE AND PROTEIN DRUGS side chains: – MW, type and number of side chains determine its acidity and polarity (pharmacokinetics) metabolized extensively = very poor oral absorption and short half-life – parenteral instead of oral route of administration KAR Lanzon, RPh