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The Organic Chemistry of Drug Design and Drug Action
2nd Edition - January 12, 2004
Author: Richard B. Silverman
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Standard medicinal chemistry courses and texts are organized by classes of drugs with an emphasis on descriptions of their biological and pharmacological effects. This book… Read more
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Standard medicinal chemistry courses and texts are organized by classes of drugs with an emphasis on descriptions of their biological and pharmacological effects. This book represents a new approach based on physical organic chemical principles and reaction mechanisms that allow the reader to extrapolate to many related classes of drug molecules. The Second Edition reflects the significant changes in the drug industry over the past decade, and includes chapter problems and other elements that make the book more useful for course instruction.
New edition includes new chapter problems and exercises to help students learn, plus extensive references and illustrations
Clearly presents an organic chemist's perspective of how drugs are designed and function, incorporating the extensive changes in the drug industry over the past ten years
Well-respected author has published over 200 articles, earned 21 patents, and invented a drug that is under consideration for commercialization
Advanced undergraduate and graduate students in organic-bioorganic and medicinal chemistry. Synthetic organic chemists. Practicing chemists in these fields working in the area of drug discovery and development
PREFACE CHAPTER 1 Introduction I. Medicinal Chemistry Folklore II. Discovery of New Drugs General References References CHAPTER 2 Drug Discovery, Design, and Development I. Drug Discovery A. Drug Discovery Without a Lead 1. Penicillins 2. Librium B. Lead Discovery 1. Random Screening 2. Non-Random Screening 3. Drug Metabolism Studies 4. Clinical Observations 5. Rational Approaches to Lead Discovery II. Lead Modification: Drug Design And Development A. Identification of the Active Part: The Pharmacophore B. Functional Group Modification C. Structure-Activity Relationships (SAR) D. Privileged Structures and Drug-Like Molecules E. Structure Modification to Increase Potency and Therapeutic Index 1. Homologation 2. Chain Branching 3. Ring-chain Transformations 4. Bioisosterism 5. Combinatorial Chemistry a. General Aspects b. Split synthesis: peptide libraries c. Encoding combinatorial libraries d. Nonpeptide libraries 6. SAR by NMR/ SAR by MS 7. Peptidomimetics F. Structure Modifications to Increase Oral Bioavailability 1. Electronic Effects: The Hammett Equation 2. Lipophilicity Effects a. Importance of Lipophilicity b. Measurement of Lipophilicities c. Computerization of log P Values d. Membrane Lipophilicity 3. Effects of Ionization on Lipophilicity and Oral Bioavailability 4. Other Properties that Influence Oral Bioavailability and Ability to Cross the Blood-Brain Barrier G. Quantitative Structure-Activity Relationships (QSAR) 1. Historical 2. Steric Effects: The Taft Equation and Other Equations 3. Methods Used to Correlate Physicochemical Parameters with Biological Activity a. Hansch analysis: A linear multiple regression analysis b. Free and Wilson or de novo method c. Enhancement factor d. Manual stepwise methods: Topliss operational schemes and others e. Batch selection methods: Batchwise Topliss operational scheme, cluster analysis, and others 4. Computer-Based Methods of QSAR Related to Receptor Binding: 3D- QSAR H. Molecular Graphics-Based Drug Design I. Epilogue General References References CHAPTER 3 Receptors I. Introduction II. Receptor Structure A. Historical B. What is a Receptor? III. Drug-Receptor Interactions A. General Considerations B. Interactions (Forces) Involved in the Drug-Receptor Complex 1. Covalent Bonds 2. Ionic (Or Electrostatic) Interactions 3. Ion-Dipole And Dipole-Dipole Interactions 4. Hydrogen Bonds 5. Charge-Transfer Complexes 6. Hydrophobic Interactions 7. Van der Waals Or London Dispersion Forces 8. Conclusion C. Determination of Drug-Receptor Interactions D. Drug-Receptor Theories 1. Occupancy Theory 2. Rate Theory 3. Induced-Fit Theory 4. Macromolecular Perturbation Theory 5. Activation-Aggregation Theory 6. The Two-State (Multi-State) Model of Receptor Activation E. Topographical and Stereochemical Considerations 1. Spatial Arrangement of Atoms 2. Drug and Receptor Chirality 3. Geometric Isomers 4. Conformational Isomers 5. Ring Topology F. Ion Channel Blockers G. Case History of Rational Drug Design of a Receptor Antagonist: Cimetidine General References References CHAPTER 4 Enzymes (Catalytic Receptors) I. Enzymes as Catalysts A. What are Enzymes? B. How do Enzymes Work? 1. Specificity of Enzyme-Catalyzed Reactions a. Binding Specificity b. Reaction Specificity 2. Rate Acceleration II. Mechanisms of Enzyme Catalysis A. Approximation B. Covalent Catalysis C. General Acid-Base Catalysis D. Electrostatic Catalysis E. Desolvation F. Strain or Distortion G. Example of the Mechanisms of Enzyme Catalysis III. Coenzyme Catalysis A. Pyridoxal 5-Phosphate (PLP) 1. Racemases 2. Decarboxylases 3. Aminotransferases (formerly Transaminases) 4. PLP-Dependent b-Elimination B. Tetrahydrofolate and Pyridine Nucleotides C. Flavin 1. Two-Electron (Carbanion) Mechanism 2. Carbanion Followed by Two-One Electron Transfers 3. One-Electron Mechanism 4. Hydride Mechanism D. Heme E. Adenosine Triphosphate and Coenzyme A IV. Enzyme Therapy General References References CHAPTER 5 Enzyme Inhibition and Inactivation I. Why Inhibit An Enzyme? II. Drug Resistance A. What is Drug Resistance? B. Mechanisms of Drug Resistance 1. Altered Drug Uptake 2. Overproduction of the Target Enzyme 3. Altered Target Enzyme (or Site of Action) 4. Production of a Drug-Destroying Enzyme 5. Deletion of a Prodrug-Activating Enzyme 6. Overproduction of the Substrate for the Target Enzyme 7. New Pathway for Formation of Product of the Target Enzyme 8. Efflux Pumps III. Drug Synergism (Drug Combination) A. What is Drug Synergism? B. Mechanisms of Drug Synergism 1. Inhibition of a Drug-Destroying Enzyme 2. Sequential Blocking 3. Inhibition of Enzymes in Different Metabolic Pathways 4. Efflux Pump Inhibitors 5. Use of Multiple Drugs for the Same Target IV. Reversible Enzyme Inhibitors A. Mechanism of Reversible Inhibition B. Selected Examples of Competitive Reversible Inhibitor Drugs 1. Simple Competitive Inhibition: Captopril, Enalapril, Lisinopril, and Other Antihypertensive Drugs a. Humoral Mechanism for Hypertension b. Lead Discovery c. Lead Modification and Mechanism of Action d. Dual-Acting Drugs: Dual-Acting Enzyme Inhibitors 2. Alternative Substrate Inhibition: Sulfonamide Antibacterial Agents (Sulfa Drugs) a. Lead Discovery b. Lead Modification c. Mechanism of Action d. Drug Resistance e. Drug Synergism C. Transition State Analogues and Multisubstrate Analogues 1. Theoretical Basis 2. Transition State Analogues a. Enalaprilat b. Pentostatin c. Multisubstrate Analogues D. Slow, Tight-Binding Inhibitors 1. Theoretical Basis 2. Enalaprilat 3. Lovastatin (Mevinolin) and Simvastatin, Antihypercholesterolemic Drugs a. Cholesterol and its Effects b. Lead Discovery c. Mechanism of Action d. Lead Modification 4. Peptidyl Trifluoromethyl Ketone Inhibitors of Human Leukocyte Elastase E. Case History of Rational Drug Design of an Enzyme Inhibitor: Ritonavir 1. Lead Discovery 2. Lead Modification V. Irreversible Enzyme Inhibitors A. Potential of Irreversible Inhibition B. Affinity Labeling Agents 1. Mechanism of Action 2. Selected Affinity Labeling Agents a. Penicillins and Cephalosporins/Cephamycins b. Aspirin C. Mechanism-Based Enzyme Inactivators 1. Theoretical Aspects 2. Potential Advantages in Drug Design Relative to Affinity Labeling Agents 3. Selected Examples of Mechanism-Based Enzyme Inactivators a. Vigabatrin, an Anticonvulsant Drug b. Eflornithine, an Antiprotozoal Drug and Beyond c. Tranylcypromine, an Antidepressant Drug d. Selegiline (L-deprenyl), an Antiparkinsonian Drug e. 5-Fluoro-2'-deoxyuridylate, Floxuridine, and 5-Fluorouracil, Antitumor Drugs General References References CHAPTER 6 DNA-Interactive Agents I. Introduction A. Basis for DNA-Interactive Drugs B. Toxicity of DNA-Interactive Drugs C. Combination Chemotherapy D. Drug Interactions E. Drug Resistance II. DNA Structure and Properties A. Basis for the Structure of DNA B. Base Tautomerization C. DNA Shapes D. DNA Conformations III. Classes of Drugs That Interact with DNA A. Reversible DNA Binders 1. External Electrostatic Binding 2. Groove Binding 3. Intercalation and Topoisomerase-Induced DNA Damage a. Amsacrine, an Acridine Analogue b. Dactinomycin, the Parent Actinomycin Analogue c. Doxorubicin (Adriamycin) and Daunorubicin (Daunomycin), Anthracycline Antitumor Antibiotics d. Bisintercalating Agents B. DNA Alkylators 1. Nitrogen Mustards a. Lead Discovery b. Chemistry of Alkylating Agents c. Lead Modification d. Drug Resistance 2. Ethylenimines 3. Methanesulfonates 4. Metabolically-Activated Alkylating Agents a. Nitrosoureas b. Triazene Antitumor Drugs c. Mitomycin C d. Leinamycin C. DNA Strand Breakers 1. Anthracycline Antitumor Antibiotics 2. Bleomycin 3. Tirapazamine 4. Enediyne Antitumor Antibiotics a. Esperamicins and Calicheamicins b. Dynemicin A c. Neocarzinostatin (Zinostatin) 5. Sequence Specificity for DNA Strand Scission IV. Epilogue to Receptor-Interactive Agents General References References CHAPTER 7 Drug Metabolism I. Introduction II. Synthesis of Radioactive Compounds III. Analytical Methods in Drug Metabolism A. Isolation B. Separation C. Identification D. Quantification IV. Pathways for Drug Deactivation and Elimination A. Introduction B. Phase I Transformations 1. Oxidative reactions a. Aromatic Hydroxylation b. Alkene Epoxidation c. Oxidations of Carbons Adjacent to sp2 Centers d. Oxidation at Aliphatic and Alicyclic Carbon Atoms e. Oxidations of Carbon-Nitrogen Systems f. Oxidations of Carbon-Oxygen Systems g. Oxidations of Carbon-Sulfur Systems h. Other Oxidative Reactions i. Alcohol and Aldehyde Oxidations 2. Reductive Reactions a. Carbonyl Reduction b. Nitro Reduction c. Azo Reduction d. Azido Reduction e. Tertiary Amine Oxide Reduction f. Reductive Dehalogenation 3. Carboxylation Reaction 4. Hydrolytic Reactions C. Phase II Transformations: Conjugation Reactions 1. Introduction 2. Glucuronic acid conjugation 3. Sulfate conjugation 4. Amino acid conjugation 5. Glutathione conjugation 6. Water conjugation 7. Acetyl conjugation 8. Fatty Acid and Cholesterol Conjugation 9. Methyl conjugation D. Hard and Soft Drugs General References References CHAPTER 8 Prodrugs and Drug Delivery Systems I. Enzyme Activation of Drugs A. Utility of Prodrugs 1. Aqueous Solubility 2. Absorption and Distribution 3. Site Specificity 4. Instability 5. Prolonged Release 6. Toxicity 7. Poor Patient Acceptability 8. Formulation Problems B. Types of Prodrugs II. Mechanisms of Drug Inactivation A. Carrier-linked Prodrugs 1. Carrier Linkages for Various Functional Groups a. Alcohols, Carboxylic Acids, and Related b. Amines c. Sulfonamides d. Carbonyl Compounds 2. Examples of Carrier-Linked Bipartate Prodrugs a. Prodrugs for Increased Water Solubility b. Prodrugs for Improved Absorption and Distribution c. Prodrugs for Site Specificity d. Prodrugs for Stability e. Prodrugs for Slow and Prolonged Release f. Prodrugs to Minimize Toxicity g. Prodrugs to Encourage Patient Acceptance h. Prodrugs to Eliminate Formulation Problems 3. Macromolecular Drug Carrier Systems a. General Strategy b. Synthetic Polymers c. Poly(a-amino acids) d. Other Macromolecular Supports 4. Tripartate Prodrugs 5. Mutual Prodrugs B. Bioprecursor Prodrugs 1. Origins 2. Proton Activation: An Abbreviated Case History of the Discovery of Omeprazole 3. Hydrolytic Activation 4. Elimination Activation 5. Oxidative Activation a. N- and O-Dealkylations b. Oxidative Deamination c. N-Oxidation d. S-Oxidations e. Aromatic Hydroxylation f. Other Oxidations 6. Reductive Activation a. Azo Reduction b. Azido Reduction c. Sulfoxide Reduction d. Disulfide Reduction e. Nitro Reduction 7. Nucleotide Activation 8. Phosphorylation Activation 9. Sulfation Activation 10. Decarboxylation Activation General References References INDEX
No. of pages: 640
Published: January 12, 2004
Imprint: Academic Press
Hardback ISBN: 9780126437324
eBook ISBN: 9780080513379
Richard B. Silverman
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.