The Organic Chemistry of Drug Design and Drug Action, Third Edition, represents a unique approach to medicinal chemistry based on physical organic chemical principles and reaction mechanisms that rationalize drug action, which allows reader to extrapolate those core principles and mechanisms to many related classes of drug molecules.
This new edition includes updates to all chapters, including new examples and references. It reflects significant changes in the process of drug design over the last decade and preserves the successful approach of the previous editions while including significant changes in format and coverage.
This text is designed for undergraduate and graduate students in chemistry studying medicinal chemistry or pharmaceutical chemistry; research chemists and biochemists working in pharmaceutical and biotechnology industries.
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1. Introduction 1.1. Overview 1.2. Drugs Discovered without Rational Design 1.2.1. Medicinal Chemistry Folklore 1.2.2. Discovery of Penicillins 1.2.3. Discovery of Librium 1.2.4. Discovery of Drugs through Metabolism Studies 1.2.5. Discovery of Drugs through Clinical Observations 1.3. Overview of Modern Rational Drug Design 1.3.1. Overview of Drug Targets 1.3.2. Identification and Validation of Targets for Drug Discovery 1.3.3. Alternatives to Target-Based Drug Discovery 1.3.4. Lead Discovery 1.3.5. Lead Modification (Lead Optimization) 188.8.131.52. Potency 184.108.40.206. Selectivity 220.127.116.11. Absorption, Distribution, Metabolism, and Excretion (ADME) 18.104.22.168. Intellectual Property Position 1.3.6. Drug Development 22.214.171.124. Preclinical Development 126.96.36.199. Clinical Development (Human Clinical Trials) 188.8.131.52. Regulatory Approval to Market the Drug 1.4. Epilogue 1.5. General References 1.6. Problems References 2. Lead Discovery and Lead Modification 2.1. Lead Discovery 2.1.1. General Considerations 2.1.2. Sources of Lead Compounds 184.108.40.206. Endogenous Ligands 220.127.116.11. Other Known Ligands 18.104.22.168. Screening of Compounds 22.214.171.124.1. Sources of Compounds for Screening 126.96.36.199.1.1. Natural Products 188.8.131.52.1.2. Medicinal Chemistry Collections and Other "Handcrafted" Compounds 184.108.40.206.1.3. High-Throughput Organic Synthesis 220.127.116.11.1.3.1. Solid-Phase Library Synthesis 18.104.22.168.1.3.2. Solution-Phase Library Synthesis 22.214.171.124.1.3.3. Evolution of HTOS 126.96.36.199.2. Drug-Like, Lead-Like, and Other Desirable Properties of Compounds for Screening 188.8.131.52.3. Random Screening 184.108.40.206.4. Targeted (or Focused) Screening, Virtual Screening, and Computational Methods in Lead Discovery 220.127.116.11.4.1. Virtual Screening Database 18.104.22.168.4.2. Virtual Screening Hypothesis 22.214.171.124.5. Hit-To-Lead Process 126.96.36.199.6. Fragment-based Lead Discovery 2.2. Lead Modification 2.2.1. Identification of the Active Part: The Pharmacophore 2.2.2. Functional Group Modification 2.2.3. Structure-Activity Relationships 2.2.4. Structure Modifications to Increase Potency, Therapeutic Index, and ADME Properties 188.8.131.52. Homologation 184.108.40.206. Chain Branching 220.127.116.11. Bioisosterism 18.104.22.168. Conformational Constraints and Ring-Chain Transformations 22.214.171.124. Peptidomimetics 2.2.5. Structure Modifications to Increase Oral Bioavailability and Membrane Permeability 126.96.36.199. Electronic Effects: The Hammett Equation 188.8.131.52. Lipophilicity Effects 184.108.40.206.1. Importance of Lipophilicity 220.127.116.11.2. Measurement of Lipophilicities 18.104.22.168.3. Computer Automation of log P Determination 22.214.171.124.4. Membrane Lipophilicity 126.96.36.199. Balancing Potency of Ionizable Compounds with Lipophilicity and Oral Bioavailability 188.8.131.52. Properties that Influence Ability to Cross the Blood-Brain Barrier 184.108.40.206. Correlation of Lipophilicity with Promiscuity and Toxicity 2.2.6. Computational Methods in Lead Modification 220.127.116.11. Overview 18.104.22.168. Quantitative Structure-Activity Relationships (QSARs) 22.214.171.124.1. Historical Overview. Steric Effects: The Taft Equation and Other Equations 126.96.36.199.2. Methods Used to Correlate Physicochemical Parameters with Biological Activity 188.8.131.52.2.1. Hansch Analysis: A Linear Multiple Regression Analysis 184.108.40.206.2.2. Manual Stepwise Methods: Topliss Operational Schemes and Others 220.127.116.11.2.3. Batch Selection Methods: Batchwise Topliss Operational Scheme, Cluster Analysis, and Others 18.104.22.168.2.4. Free and Wilson or de Novo Method 22.214.171.124.2.5. Computational Methods for ADME Descriptors 126.96.36.199. Scaffold Hopping 188.8.131.52. Molecular Graphics-Based Lead Modification 2.2.7. Epilogue 2.3. General References 2.4. Problems References 3. Receptors 3.1. Introduction 3.2. Drug-Receptor Interactions 3.2.1. General Considerations 3.2.2. Important Interactions (Forces) Involved in the Drug-Receptor Complex 184.108.40.206. Covalent Bonds 220.127.116.11. Ionic (or Electrostatic) Interactions 18.104.22.168. Ion-Dipole and Dipole-Dipole Interactions 22.214.171.124. Hydrogen Bonds 126.96.36.199. Charge-Transfer Complexes 188.8.131.52. Hydrophobic Interactions 184.108.40.206. Cation-? Interaction 220.127.116.11. Halogen Bonding 18.104.22.168. van der Waals or London Dispersion Forces 22.214.171.124. Conclusion 3.2.3. Determination of Drug-Receptor Interactions 3.2.4. Theories for Drug-Receptor Interactions 126.96.36.199. Occupancy Theory 188.8.131.52. Rate Theory 184.108.40.206. Induced-Fit Theory 220.127.116.11. Macromolecular Perturbation Theory 18.104.22.168. Activation-Aggregation Theory 22.214.171.124. The Two-State (Multistate) Model of Receptor Activation 3.2.5. Topographical and Stereochemical Considerations 126.96.36.199. Spatial Arrangement of Atoms 188.8.131.52. Drug and Receptor Chirality 184.108.40.206. Diastereomers 220.127.116.11. Conformational Isomers 18.104.22.168. Atropisomers 22.214.171.124. Ring Topology 3.2.6. Case History of the Pharmacodynamically Driven Design of a Receptor Antagonist: Cimetidine 3.2.7. Case History of the Pharmacokinetically Driven Design of Suvorexant 3.3. General References 3.4. Problems References 4. Enzymes 4.1. Enzymes as Catalysts 4.1.1. What are Enzymes? 4.1.2. How do Enzymes Work? 126.96.36.199. Specificity of Enzyme-Catalyzed Reactions 188.8.131.52.1. Binding Specificity 184.108.40.206.2. Reaction Specificity 220.127.116.11. Rate Acceleration 4.2. Mechanisms of Enzyme Catalysis 4.2.1. Approximation 4.2.2. Covalent Catalysis 4.2.3. General Acid-Base Catalysis 4.2.4. Electrostatic Catalysis 4.2.5. Desolvation 4.2.6. Strain or Distortion 4.2.7. Example of the Mechanisms of Enzyme Catalysis 4.3. Coenzyme Catalysis 4.3.1. Pyridoxal 5'-Phosphate 18.104.22.168. Racemases 22.214.171.124. Decarboxylases 126.96.36.199. Aminotransferases (Formerly Transaminases) 188.8.131.52. PLP-Dependent ?-Elimination 4.3.2. Tetrahydrofolate and Pyridine Nucleotides 4.3.3. Flavin 184.108.40.206. Two-Electron (Carbanion) Mechanism 220.127.116.11. Carbanion Followed by Two One-Electron Transfers 18.104.22.168. One-Electron Mechanism 22.214.171.124. Hydride Mechanism 4.3.4. Heme 4.3.5. Adenosine Triphosphate and Coenzyme A 4.4. Enzyme Catalysis in Drug Discovery 4.4.1. Enzymatic Synthesis of Chiral Drug Intermediates 4.4.2. Enzyme Therapy 4.5. General References 4.6. Problems References 5. Enzyme Inhibition and Inactivation 5.1. Why Inhibit an Enzyme? 5.2. Reversible Enzyme Inhibitors 5.2.1. Mechanism of Reversible Inhibition 5.2.2. Selected Examples of Competitive Reversible Inhibitor Drugs 126.96.36.199. Simple Competitive Inhibition 188.8.131.52.1. Epidermal Growth Factor Receptor Tyrosine Kinase as a Target for Cancer 184.108.40.206.2. Discovery and Optimization of EGFR Inhibitors 220.127.116.11. Stabilization of an Inactive Conformation: Imatinib, an Antileukemia Drug 18.104.22.168.1. The Target: Bcr-Abl, a Constitutively Active Kinase 22.214.171.124.2. Lead Discovery and Modification 126.96.36.199.3. Binding Mode of Imatinib to Abl Kinase 188.8.131.52.4. Inhibition of Other Kinases by Imatinib 184.108.40.206. Alternative Substrate Inhibition: Sulfonamide Antibacterial Agents (Sulfa Drugs) 220.127.116.11.1. Lead Discovery 18.104.22.168.2. Lead Modification 22.214.171.124.3. Mechanism of Action 5.2.3. Transition State Analogs and Multisubstrate Analogs 126.96.36.199. Theoretical Basis 188.8.131.52. Transition State Analogs 184.108.40.206.1. Enalaprilat 220.127.116.11.2. Pentostatin 18.104.22.168.3. Forodesine and DADMe-ImmH 22.214.171.124.4. Multisubstrate Analogs 5.2.4. Slow, T ight-Binding Inhibitors 126.96.36.199. Theoretical Basis 188.8.131.52. Captopril, Enalapril, Lisinopril, and Other Antihypertensive Drugs 184.108.40.206.1. Humoral Mechanism for Hypertension 220.127.116.11.2. Lead Discovery 18.104.22.168.3. Lead Modification and Mechanism of Action 22.214.171.124.4. Dual-Acting Drugs: Dual-Acting Enzyme Inhibitors 126.96.36.199. Lovastatin (Mevinolin) and Simvastatin, Antihypercholesterolemic Drugs 188.8.131.52.1. Cholesterol and Its Effects 184.108.40.206.2. Lead Discovery 220.127.116.11.3. Mechanism of Action 18.104.22.168.4. Lead Modification 22.214.171.124. Saxagliptin, a Dipeptidyl Peptidase-4 Inhibitor and Antidiabetes Drug 5.2.5. Case History of Rational Drug Design of an Enzyme Inhibitor: Ritonavir 126.96.36.199. Lead Discovery 188.8.131.52. Lead Modification 5.3. Irreversible Enzyme Inhibitors 5.3.1. Potential of Irreversible Inhibition 5.3.2. Affinity Labeling Agents 184.108.40.206. Mechanism of Action 220.127.116.11. Selected Affinity Labeling Agents 18.104.22.168.1. Penicillins and Cephalosporins/Cephamycins 22.214.171.124.2. Aspirin 5.3.3. Mechanism-Based Enzyme Inactivators 126.96.36.199. Theoretical Aspects 188.8.131.52. Potential Advantages in Drug Design Relative to Affinity Labeling Agents 184.108.40.206. Selected Examples of Mechanism-Based Enzyme Inactivators 220.127.116.11.1. Vigabatrin, an Anticonvulsant Drug 18.104.22.168.2. Eflornithine, an Antiprotozoal Drug and Beyond 22.214.171.124.3. Tranylcypromine, an Antidepressant Drug 126.96.36.199.4. Selegiline (l-Deprenyl) and Rasagiline: Antiparkinsonian Drugs 188.8.131.52.5. 5-Fluoro-2'-deoxyuridylate, Floxuridine, and 5-Fluorouracil: Antitumor Drugs 5.4. General References 5.5. Problems References 6. DNA-Interactive Agents 6.1. Introduction 6.1.1. Basis for DNA-Interactive Drugs 6.1.2. Toxicity of DNA-Interactive Drugs 6.1.3. Combination Chemotherapy 6.1.4. Drug Interactions 6.1.5. Drug Resistance 6.2. DNA Structure and Properties 6.2.1. Basis for the Structure of DNA 6.2.2. Base Tautomerization 6.2.3. DNA Shapes 6.2.4. DNA Conformations 6.3. Classes of Drugs that Interact with DNA 6.3.1. Reversible DNA Binders 184.108.40.206. External Electrostatic Binding 220.127.116.11. Groove Binding 18.104.22.168. Intercalation and Topoisomerase-Induced DNA Damage 22.214.171.124.1. Amsacrine, an Acridine Analog 126.96.36.199.2. Dactinomycin, the Parent Actinomycin Analog 188.8.131.52.3. Doxorubicin (Adriamycin) and Daunorubicin (Daunomycin), Anthracycline Antitumor Antibiotics 184.108.40.206.4. Bis-intercalating Agents 6.3.2. DNA Alkylators 220.127.116.11. Nitrogen Mustards 18.104.22.168.1. Lead Discovery 22.214.171.124.2. Chemistry of Alkylating Agents 126.96.36.199.3. Lead Modification 188.8.131.52. Ethylenimines 184.108.40.206. Methanesulfonates 220.127.116.11. (+)-CC-1065 and Duocarmycins 18.104.22.168. Metabolically Activated Alkylating Agents 22.214.171.124.1. Nitrosoureas 126.96.36.199.2. Triazene Antitumor Drugs 188.8.131.52.3. Mitomycin C 184.108.40.206.4. Leinamycin 6.3.3. DNA Strand Breakers 220.127.116.11. Anthracycline Antitumor Antibiotics 18.104.22.168. Bleomycin 22.214.171.124. Tirapazamine 126.96.36.199. Enediyne Antitumor Antibiotics 188.8.131.52.1. Esperamicins and Calicheamicins 184.108.40.206.2. Dynemicin A 220.127.116.11.3. Neocarzinostatin (Zinostatin) 18.104.22.168. Sequence Specificity for DNA-Strand Scission 6.4. General References 6.5. Problems References 7. Drug Resistance and Drug Synergism 7.1. Drug Resistance 7.1.1. What is Drug Resistance? 7.1.2. Mechanisms of Drug Resistance 22.214.171.124. Altered Target Enzyme or Receptor 126.96.36.199. Overproduction of the Target Enzyme or Receptor 188.8.131.52. Overproduction of the Substrate or Ligand for the Target Protein 184.108.40.206. Increased Drug-Destroying Mechanisms 220.127.116.11. Decreased Prodrug-Activating Mechanism 18.104.22.168. Activation of New Pathways Circumventing the Drug Effect 22.214.171.124. Reversal of Drug Action 126.96.36.199. Altered Drug Distribution to the Site of Action 7.2. Drug Synergism (Drug Combination) 7.2.1. What is Drug Synergism? 7.2.2. Mechanisms of Drug Synergism 188.8.131.52. Inhibition of a Drug-Destroying Enzyme 184.108.40.206. Sequential Blocking 220.127.116.11. Inhibition of Targets in Different Pathways 18.104.22.168. Efflux Pump Inhibitors 22.214.171.124. Use of Multiple Drugs for the Same Target 7.3. General References 7.4. Problems References 8. Drug Metabolism 8.1. Introduction 8.2. Synthesis of Radioactive Compounds 8.3. Analytical Methods in Drug Metabolism 8.3.1. Sample Preparation 8.3.2. Separation 8.3.3. Identification 8.3.4. Quantification 8.4. Pathways for Drug Deactivation and Elimination 8.4.1. Introduction 8.4.2. Phase I Transformations 126.96.36.199. Oxidative Reactions 188.8.131.52.1. Aromatic Hydroxylation 184.108.40.206.2. Alkene Epoxidation 220.127.116.11.3. Oxidations of Carbons Adjacent to sp2 Centers 18.104.22.168.4. Oxidation at Aliphatic and Alicyclic Carbon Atoms 22.214.171.124.5. Oxidations of Carbon-Nitrogen Systems 126.96.36.199.6. Oxidations of Carbon-Oxygen Systems 188.8.131.52.7. Oxidations of Carbon-Sulfur Systems 184.108.40.206.8. Other Oxidative Reactions 220.127.116.11.9. Alcohol and Aldehyde Oxidations 18.104.22.168. Reductive Reactions 22.214.171.124.1. Carbonyl Reduction 126.96.36.199.2. Nitro Reduction 188.8.131.52.3. Azo Reduction 184.108.40.206.4. Azido Reduction 220.127.116.11.5. Tertiary Amine Oxide Reduction 18.104.22.168.6. Reductive Dehalogenation 22.214.171.124. Carboxylation Reaction 126.96.36.199. Hydrolytic Reactions 8.4.3. Phase II Transformations: Conjugation Reaction 188.8.131.52. Introduction 184.108.40.206. Glucuronic Acid Conjugation 220.127.116.11. Sulfate Conjugation 18.104.22.168. Amino Acid Conjugation 22.214.171.124. Glutathione Conjugation 126.96.36.199. Water Conjugation 188.8.131.52. Acetyl Conjugation 184.108.40.206. Fatty Acid and Cholesterol Conjugation 220.127.116.11. Methyl Conjugation 8.4.4. Toxicophores and Reactive Metabolites (RMs) 8.4.5. Hard and Soft (Antedrugs) Drugs 8.5. General References 8.6. Problems References 9. Prodrugs and Drug Delivery Systems 9.1. Enzyme Activation of Drugs 9.1.1. Utility of Prodrugs 18.104.22.168. Aqueous Solubility 22.214.171.124. Absorption and Distribution 126.96.36.199. Site Specificity 188.8.131.52. Instability 184.108.40.206. Prolonged Release 220.127.116.11. Toxicity 18.104.22.168. Poor Patient Acceptability 22.214.171.124. Formulation Problems 9.1.2. Types of Prodrugs 9.2. Mechanisms of Drug Inactivation 9.2.1. Carrier-Linked Prodrugs 126.96.36.199. Carrier Linkages for Various Functional Groups 188.8.131.52.1. Alcohols, Carboxylic Acids, and Related 184.108.40.206.2. Amines and Amidines 220.127.116.11.3. Sulfonamides 18.104.22.168.4. Carbonyl Compounds 22.214.171.124. Examples of Carrier-Linked Bipartite Prodrugs 126.96.36.199.1. Prodrugs for Increased Water Solubility 188.8.131.52.2. Prodrugs for Improved Absorption and Distribution 184.108.40.206.3. Prodrugs for Site Specificity 220.127.116.11.4. Prodrugs for Stability 18.104.22.168.5. Prodrugs for Slow and Prolonged Release 22.214.171.124.6. Prodrugs to Minimize Toxicity 126.96.36.199.7. Prodrugs to Encourage Patient Acceptance 188.8.131.52.8. Prodrugs to Eliminate Formulation Problems 184.108.40.206. Macromolecular Drug Carrier Systems 220.127.116.11.1. General Strategy 18.104.22.168.2. Synthetic Polymers 22.214.171.124.3. Poly(?-Amino Acids) 126.96.36.199.4. Other Macromolecular Supports 188.8.131.52. Tripartite Prodrugs 184.108.40.206. Mutual Prodrugs (also called Codrugs) 9.2.2. Bioprecursor Prodrugs 220.127.116.11. Origins 18.104.22.168. Proton Activation: An Abbreviated Case History of the Discovery of Omeprazole 22.214.171.124. Hydrolytic Activation 126.96.36.199. Elimination Activation 188.8.131.52. Oxidative Activation 184.108.40.206.1. N- and O-Dealkylations 220.127.116.11.2. Oxidative Deamination 18.104.22.168.3. N-Oxidation 22.214.171.124.4. S-Oxidation 126.96.36.199.5. Aromatic Hydroxylation 188.8.131.52.6. Other Oxidations 184.108.40.206. Reductive Activation 220.127.116.11.5. Nitro Reduction 18.104.22.168. Nucleotide Activation 22.214.171.124. Phosphorylation Activation 126.96.36.199. Sulfation Activation 188.8.131.52. Decarboxylation Activation 9.3. General References 9.4. Problems References Appendix Index
Professor Richard B. Silverman received his B.S. degree in chemistry from The Pennsylvania State University in 1968 and his Ph.D. degree in organic chemistry from Harvard University in 1974 (with time off for a two-year military obligation from 1969-1971). After two years as a NIH postdoctoral fellow in the laboratory of the late Professor Robert Abeles in the Graduate Department of Biochemistry at Brandeis University, he joined the chemistry faculty at Northwestern University. In 1986, he became Professor of Chemistry and Professor of Biochemistry, Molecular Biology, and Cell Biology. In 2001, he became the Charles Deering McCormick Professor of Teaching Excellence for three years, and since 2004 he has been the John Evans Professor of Chemistry. His research can be summarized as investigations of the molecular mechanisms of action, rational design, and syntheses of potential medicinal agents acting on enzymes and receptors.
His awards include DuPont Young Faculty Fellow (1976), Alfred P. Sloan Research Fellow (1981-1985), NIH Research Career Development Award (1982-1987), Fellow of the American Institute of Chemists (1985), Fellow of the American Association for the Advancement of Science (1990), Arthur C. Cope Senior Scholar Award of the American Chemical Society (2003), Alumni Fellow Award from Pennsylvania State University (2008), Medicinal Chemistry Hall of Fame of the American Chemical Society (2009), the Perkin Medal from the Society of Chemical Industry (2009), the Hall of Fame of Central High School of Philadelphia (2011), the E.B. Hershberg Award for Important Discoveries in Medicinally Active Substances from the American Chemical Society (2011), Fellow of the American Chemical Society (2011), Sato Memorial International Award of the Pharmaceutical Society of Japan (2012), Roland T. Lakey Award of Wayne State University (2013), BMS-Edward E. Smissman Award of the American Chemical Society (2013), the Centenary Prize of the Royal Society of Chemistry (2013), and the Excellence in Medicinal Chemistry Prize of the Israel Chemical Society (2014).
Professor Silverman has published over 320 research and review articles, holds 49 domestic and foreign patents, and has written four books (The Organic Chemistry of Drug Design and Drug Action is translated into German and Chinese). He is the inventor of LyricaTM, a drug marketed by Pfizer for epilepsy, neuropathic pain, fibromyalgia, and spinal cord injury pain; currently, he has another CNS drug in clinical trials.Mark W. Holladay Ambit Biosciences, San Diego, CA, USA.
Dr. Mark W. Holladay is Vice President of Drug Discovery and Medicinal Chemistry at Ambit Biosciences (San Diego, California) where he leads drug discovery programs in oncology and autoimmune diseases and has contributed to compounds in clinical development. He began his drug hunting career at Abbott Laboratories where he achieved the position of Volwiler Associate Research Fellow as a medicinal chemist and project leader in the Neurosciences Research Area. He also conducted collaborative drug discovery research as a member of contract research organizations including Biofocus and Discovery Partners International. He is a co-author on over 70 peer-reviewed research articles, reviews, or chapters and is named as an inventor on over 40 patents and patent applications. Dr. Holladay earned his undergraduate degree from Vanderbilt University, his Ph.D. at Northwestern University under the direction of Professor Richard B. Silverman, and conducted postdoctoral studies with Professor Daniel H. Rich at the University of Wisconsin-Madison.