The Organic Chemistry of Drug Design and Drug Action

PREFACECHAPTER 1IntroductionI. Medicinal Chemistry FolkloreII. Discovery of New DrugsGeneral ReferencesReferencesCHAPTER 2Drug Discovery, Design, and DevelopmentI. 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 DiscoveryII. 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. EpilogueGeneral ReferencesReferencesCHAPTER 3ReceptorsI. IntroductionII. 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: CimetidineGeneral ReferencesReferencesCHAPTER 4Enzymes (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 AccelerationII. 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 CatalysisIII. 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 AIV. Enzyme TherapyGeneral ReferencesReferencesCHAPTER 5Enzyme Inhibition and InactivationI. 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 PumpsIII. 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 TargetIV. 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 ModificationV. 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 DrugsGeneral ReferencesReferencesCHAPTER 6DNA-Interactive AgentsI. Introduction A. Basis for DNA-Interactive Drugs B. Toxicity of DNA-Interactive Drugs C. Combination Chemotherapy D. Drug Interactions E. Drug ResistanceII. DNA Structure and Properties A. Basis for the Structure of DNA B. Base Tautomerization C. DNA Shapes D. DNA ConformationsIII. Classes of Drugs That Interact with DNA A. Reversible DNA Binders 1. External Electrostatic Binding 2. Groove Binding3. 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. Methanesulfonates4. Metabolically-Activated Alkylating Agentsa. Nitrosoureas b. Triazene Antitumor Drugsc. Mitomycin Cd. Leinamycin C. DNA Strand Breakers 1. Anthracycline Antitumor Antibiotics2. Bleomycin3. Tirapazamine 4. Enediyne Antitumor Antibiotics a. Esperamicins and Calicheamicins b. Dynemicin A c. Neocarzinostatin (Zinostatin)5. Sequence Specificity for DNA Strand ScissionIV. Epilogue to Receptor-Interactive AgentsGeneral ReferencesReferencesCHAPTER 7Drug MetabolismI. IntroductionII. Synthesis of Radioactive CompoundsIII. Analytical Methods in Drug Metabolism A. Isolation B. Separation C. Identification D. QuantificationIV. 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 ReferencesReferencesCHAPTER 8 Prodrugs and Drug Delivery SystemsI. 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 ProdrugsII. Mechanisms of Drug Inactivation A. Carrier-linked Prodrugs 1. Carrier Linkages for Various Functional Groups a. Alcohols, Carboxylic Acids, and Related b. Aminesc. Sulfonamidesd. 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 Prodrugs1. Origins2. Proton Activation: An Abbreviated Case History of the Discovery of Omeprazole3. Hydrolytic Activation4. Elimination Activation 5. Oxidative Activation a. N- and O-Dealkylations b. Oxidative Deamination c. N-Oxidation d. S-Oxidationse. Aromatic Hydroxylationf. Other Oxidations 6. Reductive Activationa. Azo Reductionb. Azido Reduction c. Sulfoxide Reduction d. Disulfide Reduction e. Nitro Reduction 7. Nucleotide Activation8. Phosphorylation Activation 9. Sulfation Activation 10. Decarboxylation ActivationGeneral ReferencesReferencesINDEX