RETROMETABOLIC DRUG DESIGN AND TARGETING -- Contents -- Preface -- 1 Introduction -- 1.1 New Drugs and Medical Progress -- 1.2 The Challenge of New Drug Discovery -- References -- 2 Mechanism of Drug Action: Basic Concepts -- 2.1 Pharmacodynamic Phase: Drug-Receptor Interactions -- 2.1.1 The Receptor Concept and Receptor Types -- 2.1.2 Ligand-Receptor Binding -- 2.1.3 Receptor Occupancy and Activation -- 2.2 Pharmacokinetic Phase: ADME -- 2.2.1 Drug Absorption and Distribution -- 2.2.2 Drug Metabolism and Excretion -- 2.2.3 Basic Pharmacokinetic Concepts -- 2.3 Structural Requirements: Keeping It "Drug-Like" -- 2.3.1 The Drug-Like Chemical Space -- 2.3.2 Oral Drugs: The Challenge of Bioavailability -- References -- 3 The Drug Discovery and Development Process -- 3.1 Discovery Research -- 3.1.1 Prediscovery -- 3.1.2 Target Identification -- 3.1.3 Target Validation -- 3.1.4 Target-to-Hit and Hit-to-Lead Development -- 3.1.5 Early Distribution and Safety Tests -- 3.1.6 Lead Optimization -- 3.2 Preclinical Development -- 3.2.1 Preclinical Testing -- 3.2.2 Investigational New Drug Application and Safety -- 3.3 Clinical Development -- 3.3.1 Phase I Clinical Trials -- 3.3.2 Phase II Clinical Trials -- 3.3.3 Phase III Clinical Trials -- 3.4 Regulatory Approval and PostMarketing Development -- 3.4.1 New Drug Application and Regulatory Approval -- 3.4.2 Manufacturing -- 3.4.3 Postapproval Studies and Phase IV Trials -- 3.4.4 Patent Expiration and Generic Approval -- 3.5 Problems with the Current Paradigm -- 3.5.1 Decreasing R&D Efficiency -- 3.5.2 The Drug Discovery Process: Improvements Needed -- References -- 4 Retrometabolic Drug Design -- 4.1 Design Principles -- 4.2 Terminology -- 4.2.1 Soft Drug vs. Hard Drug -- 4.2.2 Soft Drug vs. Prodrug -- 4.2.3 Chemical Delivery System vs. Prodrug -- References -- 5 Soft Drugs -- 5.1 Enzymatic Hydrolysis.

5.1.1 Esterases -- 5.1.2 Interspecies Variability -- 5.1.3 Interorgan and Interindividual Variability -- 5.1.4 Mechanism: Catalytic Triad and Oxyanion Hole -- 5.1.5 Kinetics -- 5.1.6 Stereoselectivity -- 5.1.7 Activation Energy and Temperature Dependence -- 5.1.8 Structure-Metabolism Relationships -- 5.1.9 Rate-Influencing Role of the Alcohol or Acyl Side -- 5.2 Soft Drug Approaches -- 5.3 Inactive Metabolite-Based Soft Drugs -- 5.3.1 Soft Beta-Blockers -- 5.3.2 Soft Opioid Analgetics: Remifentanil -- 5.3.3 Soft Corticosteroids -- 5.3.4 Soft Calcitriol (1α,25-Dihydroxyvitamin D3) Analogs -- 5.3.5 Soft Estrogens -- 5.3.6 Soft β2-Agonists -- 5.3.7 Soft Psychostimulants -- 5.3.8 Soft Insecticides and Pesticides -- 5.3.9 Soft Anticholinergics: Inactive Metabolite-Based Approach -- 5.4 Soft Analogs -- 5.4.1 Soft Anticholinergics: Soft Quaternary Analogs -- 5.4.2 Soft Antimicrobials -- 5.4.3 Soft Antiarrhythmic Agents -- 5.4.4 Soft Serotonin Receptor Agonists: Naronapride -- 5.4.5 Soft Anticoagulants (Vitamin K Antagonists):Tecarfarin -- 5.4.6 Soft Angiotensin Converting Enzyme Inhibitors -- 5.4.7 Soft Dihydrofolate Reductase Inhibitors -- 5.4.8 Soft Calcineurin Inhibitors (Soft Immunosuppressants) -- 5.4.9 Soft Cytokine Modulators -- 5.4.10 Soft Phosphodiesterase 4 Inhibitors -- 5.4.11 Soft Matrix Metalloproteinase Inhibitors -- 5.4.12 Soft Cannabinoids -- 5.4.13 Soft Benzodiazepine Analogs: Remimazolam and Analogs -- 5.4.14 Soft Anesthetics -- 5.4.15 Soft Ca2+ Channel Blockers -- 5.5 Active Metabolite-Based Soft Drugs -- 5.6 Activated Soft Drugs -- 5.7 Pro-Soft Drugs -- 5.7.1 Pro-Soft Drugs of Natural Soft Drugs: Hormone Prodrugs -- 5.7.2 Pro-Soft Drugs of Peptidyl Boronic Acid Derivatives -- 5.8 Computer-Aided Design -- 5.8.1 Computer-Aided Soft Drug Design -- 5.8.2 Predicting Molecular Properties -- 5.8.3 Molecular Size.

5.8.4 Lipophilicity: Octanol/Water Partition Coefficient -- 5.8.5 Water Solubility -- 5.8.6 Structure Generation -- 5.8.7 Candidate Ranking -- 5.8.8 Hydrolytic Lability -- 5.8.9 Illustrations -- 5.9 Soft Drugs: Summary -- References -- 6 Chemical Delivery Systems -- 6.1 Enzymatic Physicochemical-Based (Brain-Targeting) CDSs -- 6.1.1 The Challenge of Brain Targeting -- 6.1.2 The Blood-Brain Barrier -- 6.1.3 Brain-Targeting Drug Delivery Approaches -- 6.1.4 Brain-Targeting CDSs: Details -- 6.1.5 Quantifying Delivery -- 6.1.6 Genesis of the CDS Concept: Pro-2-PAM -- 6.1.7 Berberine -- 6.1.8 Dopamine CDS -- 6.1.9 Zidovudine (AZT) CDS -- 6.1.10 Other Antiviral and Antiretroviral CDSs -- 6.1.11 Anticancer CDSs -- 6.1.12 Other Brain-Targeting CDSs -- 6.1.13 Estradiol CDS -- 6.1.14 Cyclodextrin Complexes -- 6.1.15 Molecular Packaging -- 6.2 Site-Specific Enzyme-Activated (Eye-Targeting) CDSs -- 6.2.1 The Challenge of Ocular Targeting -- 6.2.2 Potential Therapeutic Applications: Glaucoma -- 6.2.3 Eye-Targeting CDSs: Design Principles -- 6.2.4 Oxime and Methoxime Analogs of Beta-Blockers -- 6.3 Receptor-Based Transient Anchor-Type CDSs -- References -- Conclusions -- Index -- Supplemental Images.