The Organic Chemistry of Drug Design and Drug Action

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Silverman, Richard B.

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.

Holladay, Mark W.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.

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)  Potency  Selectivity  Absorption, Distribution, Metabolism, and Excretion (ADME)  Intellectual Property Position      1.3.6. Drug Development  Preclinical Development  Clinical Development (Human Clinical Trials)  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  Endogenous Ligands  Other Known Ligands  Screening of Compounds       Sources of Compounds for Screening            Natural Products            Medicinal Chemistry Collections and Other "Handcrafted" Compounds            High-Throughput Organic Synthesis                 Solid-Phase Library Synthesis                 Solution-Phase Library Synthesis                 Evolution of HTOS       Drug-Like, Lead-Like, and Other Desirable Properties of Compounds for Screening       Random Screening       Targeted (or Focused) Screening, Virtual Screening, and Computational Methods in Lead Discovery            Virtual Screening Database            Virtual Screening Hypothesis       Hit-To-Lead Process       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  Homologation  Chain Branching  Bioisosterism  Conformational Constraints and Ring-Chain Transformations  Peptidomimetics      2.2.5. Structure Modifications to Increase Oral Bioavailability and Membrane Permeability  Electronic Effects: The Hammett Equation  Lipophilicity Effects       Importance of Lipophilicity       Measurement of Lipophilicities       Computer Automation of log P Determination       Membrane Lipophilicity  Balancing Potency of Ionizable Compounds with Lipophilicity and Oral Bioavailability  Properties that Influence Ability to Cross the Blood-Brain Barrier  Correlation of Lipophilicity with Promiscuity and Toxicity      2.2.6. Computational Methods in Lead Modification  Overview  Quantitative Structure-Activity Relationships (QSARs)       Historical Overview. Steric Effects: The Taft Equation and Other Equations       Methods Used to Correlate Physicochemical Parameters with Biological Activity            Hansch Analysis: A Linear Multiple Regression Analysis            Manual Stepwise Methods: Topliss Operational Schemes and Others            Batch Selection Methods: Batchwise Topliss Operational Scheme, Cluster Analysis, and Others            Free and Wilson or de Novo Method            Computational Methods for ADME Descriptors  Scaffold Hopping  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  Covalent Bonds  Ionic (or Electrostatic) Interactions  Ion-Dipole and Dipole-Dipole Interactions  Hydrogen Bonds  Charge-Transfer Complexes  Hydrophobic Interactions  Cation-? Interaction  Halogen Bonding  van der Waals or London Dispersion Forces  Conclusion      3.2.3. Determination of Drug-Receptor Interactions      3.2.4. Theories for Drug-Receptor Interactions  Occupancy Theory  Rate Theory  Induced-Fit Theory  Macromolecular Perturbation Theory  Activation-Aggregation Theory  The Two-State (Multistate) Model of Receptor Activation      3.2.5. Topographical and Stereochemical Considerations  Spatial Arrangement of Atoms  Drug and Receptor Chirality  Diastereomers  Conformational Isomers  Atropisomers  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?  Specificity of Enzyme-Catalyzed Reactions       Binding Specificity       Reaction Specificity  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  Racemases  Decarboxylases  Aminotransferases (Formerly Transaminases)  PLP-Dependent ?-Elimination      4.3.2. Tetrahydrofolate and Pyridine Nucleotides      4.3.3. Flavin  Two-Electron (Carbanion) Mechanism  Carbanion Followed by Two One-Electron Transfers  One-Electron Mechanism  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  Simple Competitive Inhibition       Epidermal Growth Factor Receptor Tyrosine Kinase as a Target for Cancer       Discovery and Optimization of EGFR Inhibitors  Stabilization of an Inactive Conformation: Imatinib, an Antileukemia Drug       The Target: Bcr-Abl, a Constitutively Active Kinase       Lead Discovery and Modification       Binding Mode of Imatinib to Abl Kinase       Inhibition of Other Kinases by Imatinib  Alternative Substrate Inhibition: Sulfonamide Antibacterial Agents (Sulfa Drugs)       Lead Discovery       Lead Modification       Mechanism of Action      5.2.3. Transition State Analogs and Multisubstrate Analogs  Theoretical Basis  Transition State Analogs       Enalaprilat       Pentostatin       Forodesine and DADMe-ImmH       Multisubstrate Analogs      5.2.4. Slow, T ight-Binding Inhibitors  Theoretical Basis  Captopril, Enalapril, Lisinopril, and Other Antihypertensive Drugs       Humoral Mechanism for Hypertension       Lead Discovery       Lead Modification and Mechanism of Action       Dual-Acting Drugs: Dual-Acting Enzyme Inhibitors  Lovastatin (Mevinolin) and Simvastatin, Antihypercholesterolemic Drugs       Cholesterol and Its Effects       Lead Discovery       Mechanism of Action       Lead Modification  Saxagliptin, a Dipeptidyl Peptidase-4 Inhibitor and Antidiabetes Drug      5.2.5. Case History of Rational Drug Design of an Enzyme Inhibitor: Ritonavir  Lead Discovery  Lead Modification 5.3. Irreversible Enzyme Inhibitors      5.3.1. Potential of Irreversible Inhibition      5.3.2. Affinity Labeling Agents  Mechanism of Action  Selected Affinity Labeling Agents       Penicillins and Cephalosporins/Cephamycins       Aspirin      5.3.3. Mechanism-Based Enzyme Inactivators  Theoretical Aspects  Potential Advantages in Drug Design Relative to Affinity Labeling Agents  Selected Examples of Mechanism-Based Enzyme Inactivators       Vigabatrin, an Anticonvulsant Drug       Eflornithine, an Antiprotozoal Drug and Beyond       Tranylcypromine, an Antidepressant Drug       Selegiline (l-Deprenyl) and Rasagiline: Antiparkinsonian Drugs       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  External Electrostatic Binding  Groove Binding  Intercalation and Topoisomerase-Induced DNA Damage       Amsacrine, an Acridine Analog       Dactinomycin, the Parent Actinomycin Analog       Doxorubicin (Adriamycin) and Daunorubicin (Daunomycin), Anthracycline Antitumor Antibiotics       Bis-intercalating Agents      6.3.2. DNA Alkylators  Nitrogen Mustards       Lead Discovery       Chemistry of Alkylating Agents       Lead Modification       Ethylenimines       Methanesulfonates       (+)-CC-1065 and Duocarmycins       Metabolically Activated Alkylating Agents            Nitrosoureas            Triazene Antitumor Drugs            Mitomycin C            Leinamycin      6.3.3. DNA Strand Breakers  Anthracycline Antitumor Antibiotics  Bleomycin  Tirapazamine  Enediyne Antitumor Antibiotics       Esperamicins and Calicheamicins       Dynemicin A       Neocarzinostatin (Zinostatin)  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  Altered Target Enzyme or Receptor  Overproduction of the Target Enzyme or Receptor  Overproduction of the Substrate or Ligand for the Target Protein  Increased Drug-Destroying Mechanisms  Decreased Prodrug-Activating Mechanism  Activation of New Pathways Circumventing the Drug Effect  Reversal of Drug Action  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  Inhibition of a Drug-Destroying Enzyme  Sequential Blocking  Inhibition of Targets in Different Pathways  Efflux Pump Inhibitors  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  Oxidative Reactions       Aromatic Hydroxylation       Alkene Epoxidation       Oxidations of Carbons Adjacent to sp2 Centers       Oxidation at Aliphatic and Alicyclic Carbon Atoms       Oxidations of Carbon-Nitrogen Systems       Oxidations of Carbon-Oxygen Systems       Oxidations of Carbon-Sulfur Systems       Other Oxidative Reactions       Alcohol and Aldehyde Oxidations  Reductive Reactions       Carbonyl Reduction       Nitro Reduction       Azo Reduction       Azido Reduction       Tertiary Amine Oxide Reduction       Reductive Dehalogenation  Carboxylation Reaction  Hydrolytic Reactions      8.4.3. Phase II Transformations: Conjugation Reaction  Introduction  Glucuronic Acid Conjugation  Sulfate Conjugation  Amino Acid Conjugation  Glutathione Conjugation  Water Conjugation  Acetyl Conjugation  Fatty Acid and Cholesterol Conjugation  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  Aqueous Solubility  Absorption and Distribution  Site Specificity  Instability  Prolonged Release  Toxicity  Poor Patient Acceptability  Formulation Problems      9.1.2. Types of Prodrugs 9.2. Mechanisms of Drug Inactivation      9.2.1. Carrier-Linked Prodrugs  Carrier Linkages for Various Functional Groups       Alcohols, Carboxylic Acids, and Related       Amines and Amidines       Sulfonamides       Carbonyl Compounds  Examples of Carrier-Linked Bipartite Prodrugs       Prodrugs for Increased Water Solubility       Prodrugs for Improved Absorption and Distribution       Prodrugs for Site Specificity       Prodrugs for Stability       Prodrugs for Slow and Prolonged Release       Prodrugs to Minimize Toxicity       Prodrugs to Encourage Patient Acceptance       Prodrugs to Eliminate Formulation Problems  Macromolecular Drug Carrier Systems       General Strategy       Synthetic Polymers       Poly(?-Amino Acids)       Other Macromolecular Supports  Tripartite Prodrugs  Mutual Prodrugs (also called Codrugs)      9.2.2. Bioprecursor Prodrugs  Origins  Proton Activation: An Abbreviated Case History of the Discovery of Omeprazole  Hydrolytic Activation  Elimination Activation  Oxidative Activation       N- and O-Dealkylations       Oxidative Deamination       N-Oxidation       S-Oxidation       Aromatic Hydroxylation       Other Oxidations  Reductive Activation       Nitro Reduction  Nucleotide Activation  Phosphorylation Activation  Sulfation Activation  Decarboxylation Activation 9.3. General References 9.4. Problems References Appendix Index

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.

  • Updates to all chapters, including new examples and references
  • Chapter 1 (Introduction): Completely rewritten and expanded as an overview of topics discussed in detail throughout the book
  • Chapter 2 (Lead Discovery and Lead Modification): Sections on sources of compounds for screening including library collections, virtual screening, and computational methods, as well as hit-to-lead and scaffold hopping; expanded sections on sources of lead compounds, fragment-based lead discovery, and molecular graphics; and deemphasized solid-phase synthesis and combinatorial chemistry
  • Chapter 3 (Receptors): Drug-receptor interactions, cation-? and halogen bonding; atropisomers; case history of the insomnia drug suvorexant
  • Chapter 4 (Enzymes): Expanded sections on enzyme catalysis in drug discovery and enzyme synthesis
  • Chapter 5 (Enzyme Inhibition and Inactivation): New case histories:
    • for competitive inhibition, the epidermal growth factor receptor tyrosine kinase inhibitor, erlotinib and Abelson kinase inhibitor, imatinib
    • for transition state analogue inhibition, the purine nucleoside phosphorylase inhibitors, forodesine and DADMe-ImmH, as well as the mechanism of the multisubstrate analog inhibitor isoniazid
    • for slow, tight-binding inhibition, the dipeptidyl peptidase-4 inhibitor, saxagliptin
  • Chapter 7 (Drug Resistance and Drug Synergism): This new chapter includes topics taken from two chapters in the previous edition, with many new examples
  • Chapter 8 (Drug Metabolism): Discussions of toxicophores and reactive metabolites
  • Chapter 9 (Prodrugs and Drug Delivery Systems): Discussion of antibody-drug conjugates

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