Medicinal Chemistry for Practitioners

JIE JACK LI, PHD has practiced medicinal chemistry since 1997 at Pfizer, BMS, and Revolution Medicines, respectively, with a four-year sojourn at the University of San Francisco as an Associate Professor, teaching medicinal and organic chemistry. He is currently a vice president at ChemPartner, splitting his time between San Francisco and Shanghai. He has authored or edited 30 books and many of those were published by Wiley, including Drug Discovery: Practices, Processes, and Perspectives, Innovative Drug Synthesis, Modern Drug Synthesis, The Art of Drug Synthesis, and Contemporary Drug Synthesis.

"The book collects an important amount of data that are presented clearly and in depth, with the support of numerous schemes and figures, making reading very fluent." -- ChemMedChem, Jan 2022

• Preface viiChapter 1. Drug Targets 11.1 Selection and Validation of Drug Targets 11.1.1 Factors to Consider 11.1.2 Target Selection 51.1.3 Target Validation 61.2 Enzymes 81.2.1 Competitive Inhibitor 81.2.2 Allosteric Inhibitors 211.2.3 Covalent Irreversible Inhibitors 281.2.4 Transition-state Mimetics 371.2.5 Suicide Substrates 421.2.6 Isozyme Selectivity of Inhibitors 451.3 Receptors 521.3.1 G-Protein-Coupled Receptors 581.3.2 Nuclear Hormone Receptors 721.3.3 Growth Factor Receptors 791.3.4 Ionotropic Receptors 801.4 Ion Channels 811.4.1 Calcium Channel Blockers 811.4.2 Sodium Channel Blockers 831.4.3 Potassium Channel Blockers 831.5 Carrier Proteins 841.6 Structural Proteins 851.7 Nucleic Acids 851.8 Protein-protein Interactions 871.9 Further Readings 891.10 References 89Chapter 2 Hit/Lead Discovery 972.1 Irrational Drug Design (Serendipity) 972.2 Natural Products 982.2.1 From Plants 982.2.2 From Animals 1012.2.3 From Microorganisms 1042.2.4 From Natural Ligands 1052.2.5 From Modifying Existing Drugs 1062.3 High Through-put Screening (HTS) 1072.4 Fragment-based Lead Discovery 1112.5 DNA-encoded Library (DEL) 1162.6 PROTAC 1182.7 Further Readings 1282.8 References 128Chapter 3. Pharmacokinetics (ADME) 1333.1 Physicochemical Properties 1333.1.1 Lipophilicity 1333.1.2 Hydrogen Bonding 1383.1.3. Polar Surface Area 1413.1.4 Rotatable Bonds 1423.1.5 Rule of 5 1433.1.6 Ligand Efficiency 1443.1.7 Lipophilic Efficiency 1453.2 Absorption 1463.2.1 Definition of Pharmacokinetics Parameters 1463.2.2 Improving Solubility 1503.2.3 Absorption by Diffusion 1563.2.4 Absorption by Active Transports 1573.2.5 Absorption by Pinocytosis 1633.3 Distribution 1643.3.1. Around the Blood Supply, to Tissues, and to Cells 1643.3.2. Blood–Brain Barrier 1673.3.3. Efflux Transporters 1703.3.4. Plasma Protein Binding 1753.4 Metabolism 1793.4.1. Overview of Drug Metabolism 1793.4.2 Cytochrome P450 Enzymes 1823.4.3. Drug–Drug Interactions 1833.4.4. Phase I Metabolism 1863.4.5. Phase II Metabolism 1983.5 Excretion 2053.5.1. Renal Excretion 2063.5.2. Non-Renal Excretion 2073.6 Pro-drugs 2093.6.1. Overcoming Formulation and Administration Problems 2093.6.2. Overcoming Absorption Barriers 2113.6.3. Overcoming Distribution Problems 2143.6.4. Overcoming Metabolism and Excretion Problems 2143.6.5. Overcoming Toxicity Problems 2153.7 Further Readings 2183.8 References 218Chapter 4 Bioisosteres 2254.1 Introduction to Bioisosteres 2254.1.1 Definition 2254.1.2 Utility 2254.2 Hydrogen Isosteres 2324.2.1 Deuterium 2324.2.2. Fluorine 2354.2.3. Chlorine 2394.2.4. Methyl 2414.2 Alkyl Isosteres 2434.3.1 O for CH2 2444.3.2 Cyclopropane as an Alkyl Isostere 2444.3.3 Silicon as an Isostere of Carbon 2464.3.4 t-Butyl Isosteres 2474.4 Alcohol, Phenol, and Thiol Isosteres 2504.4.1 Alcohol 2504.4.2 Phenol 2534.4.3. Thiol 2574.5 Carboxylic Acid and Derivative Isosteres 2584.5.1 Carboxylic Acid 2584.5.2 Hydroxamic Acid 2704.5.3 Ester and Amide 2734.5.4 Urea, Guanidine, and Amidine 2794.6 Scaffold Hopping 2824.6.1. Phenyl 2825.6.2 Biphenyl 2855.6.3 N for CH in Aromatic Rings 2865.6.4 Isosterism between Heterocycles 2904.7 Peptide Isosteres 2934.7.1 Cyclization 2944.7.2. Intramolecular Hydrogen Bonding 2954.7.3. N-Methylation 2964.7.4 Shielding 2974.8 Further Readings 2984.9 References 298Chapter 5. Structural Alerts for Toxicity 3075.1 Reactive Electrophiles 3075.1.1. Alkylating Agents 3085.1.2. Michael Acceptors 3125.1.3. Heteroaromatic Halides 3155.1.4 Miscellaneous Reactive Electrophiles 3175.2 DNA Intercalators 3185.3 Carcinogens 3195.4 Metabolism Problematic Molecules 3215.4.1 Anilines and Anilides 3215.4.2 Problematic Amines 3305.4.3 Nitroaromatics 3365.4.4 Quinones and Phenols 3405.4.5 S-Containing Compounds 3455.4.6 Hydrazines and Hydrazides 3505.4.7 Methylenedioxyphenyl Moiety 3555.4.8 Electron-rich Heteroaromatics 3605.5 PAINS 3685.5.1 Unsaturated Rhodanines 3685.5.2 Phenolic Mannich Bases 3715.5.3 Invalid Metabolic Panaceas 3735.5.4 Alkylidene Barbituates etc. 3735.6 Conclusions 3755.7 Further Readings 3755.8 References 376Index 383