The Organic Chemistry of Drug Design and Drug Action Second Edition
To Mom and the memory of Dad, for their love, their humor, their ethics, their itl-p'ilaliml but also for their genes
Contents Preface to the first edition Preface to the second Edition 1 Introduction 1.1 Medicinal Chemistry Folklore 1. 2 Discovery of New Drugs 1.3 General references 1.4 References 2 Drug Discovery, Design, and Development 2.1 Drug Discovery 112347899 2. 1.A Drug Discovery without a Lead A1 Penicilli 2.1. B Lead Discovery 11 B. 1 Random Screening 13 6.2 Nonrandom(or Targeted or Focused) Screening B3 Drug Metabolism Studies B 4 Clinical Observations B5 Rational Approaches to Lead Discovery 16 2.2 Lead Modification: Drug Design and Development 2. 2.A Identification of the Active Part: The Pharmacophore 2.2. c Structure-Activity Relationships 21 2.2. D Privileged Structures and Drug-Like Molecules 2.2.e Structure Modifications to Increase Potency and the Therapeutic Index E 1 Homologation E2 Chain branching E,3 Ring-Chain Transformations E 4 bioisosterism E5 Combinatorial Chemistry a. General Aspects b. Split Synthesis: Peptide Libraries
Encoding Combinatorial Libraries d. Nonpeptide Libraries E. SAR by NMR/SAR by Ms E 7 Pepti 2.2.F Structure Modifications to Increase Oral Bioavailability F1 Electronic Effects: The Hammett Equation licity b. Measurement of lipophil f Log P d. Membrane lipophilicity F3 Effects of Ionization on Lipophilicity and Oral Bioavailability F4 Other Properties that Influence Oral Bioavailability and Ability to Cross the blood-Brain barrier 2.2. G Quantitative Structure-Activity Relationships G 1 Historical G 2 Steric Effects: The Taft Equation and Other Equations G3 Methods Used to Correlate Physicochemical Parameters with a. Hansch Analysis: A Linear Multiple Regression Analysis ..,6X b. Free and wilson or de novo Method 70 d. Manual Stepwise Methods: Topliss Operational Schemes and Others 7 e. Batch Selection Methods: Batchwise Topliss Operational Scheme, Cluster Analysis, and Others G4 Computer-Based Methods of QSAR Related to Receptor Binding 3D-QSAR 2.2. H Molecular Graphics-Based Drug Design 2.3 General Refe 2. 4 Problems 2.5 References 10X) 3. 1 Introductio 121 3.2 Drug-Receptor Interactions 123 3.2.B Interactions(Forces) Involved in the Drug-Receptor Complex .... 124 B. 1 Covalent Bonds B2 Ionic(or Electrostatic)Interactions B3 Ion-Dipole and Dipole-Dipole Interactions B4 Hydrogen bonds B5 Charge-Transfer Complexes 125 B 6 Hydrophobic Interactions
Contents B7 Van der Waals or London Dispersion Forces B 8 Conclusion 130 3. 2.C Determination of Drug-Receptor Interactions 3. 2. Theories for Drug-Receptor Interactions 37 D 1 Occupancy Theory D 2 D, 3 Induced-Fit Theory D4 Macromolecular Perturbation Theory D5 Activation-Aggregation Theory D.6 The Two-State(Multistate)Model of Receptor Activation 3. 2. E Topographical and Stereochemical Considerations 142 E 1 Spatial Arrangement of Atoms E 2 Drug and Receptor Chirality E 3 Geometric Isomers ( Di E 4 Conformational Isomers .5 Ring Topology 3.2.F Ion Channel blockers 58 3. 2. G Case History of Rational Drug Design of a Receptor 3.5 Refer 4.1. a What Are Enzymes? 174 4.1. B How do B. 1 Specificity of Enzyme-Catalyze 176 a. Binding Specificity b. Reaction Specificity 177 B 2 Rate acceleration 178 4.2 Mechanisms of Enzyme Catalysis 4.2.A 4.2. B Covalent Catalysis 4. 2.C General Acid-Base Catalysis 4.2. Electrostatic Catalysis ,184 4.2E Desolvation 185 42.F Strain or Distortion 4.2. G Example of the Mechanisms of Enzyme Catalysis 4.3.A Pyridoxal 5-Phosphate(PLP 188 A2 Decarboxylases 195 A 3 Aminotransferases(Formerly Transaminases) A4 PLP-Dependent B-Elimination 00 4.3. B Tetrahydrofolate and Pyridine Nucleotides 43. C Flavin