Cover -- Title Page -- Copyright Page -- Table of Contents -- Chapter 1 History of Drug Discovery -- 1. Introduction -- 2. Antibacterials -- 2.1 Lister and Carbolic Acid -- 2.2 Dr. Ehrlich'c Magic Bullet -- 2.3 Domagk and Sulfa Drugs -- 2.4 Fleming, Florey, Chain, and Penicillin -- 2.5 Waksman, Schatz, and Streptomycin -- 2.6 Duggar, Conover, and Tetracyclines -- 2.7 Quinolones and Zyvox -- 3. Cancer Drugs -- 3.1 The Origin of Cancer -- 3.2 Chemotherapy -- 3.3 Hormone Treatment -- 3.4 Small-Molecule Protein Kinase Inhibitors -- 4. Cardiovascular Drags -- 4.1 Withering and Digitalis -- 4.2 Sobrero, Nobel, and Nitroglycerin -- 4.3 Vogl and Diuretics -- 4.4 Snake Venom and ACE Inhibitors -- 4.5 Black and Beta-Blockers -- 4.6 Renin Inhibitor -- 4.7 Fleckenstein and Calcium Channel Blockers -- 4.8 Blood Thinners, from Heparin to Plavix -- 5. Cholesterol Drugs -- 5.1 Early Cholesterol Drugs: Niacin and Fibrates -- 5.2 Endo, Mevastatin, and Pravachol -- 5.3 Merck's Mevacor and Zocor -- 5.4 Lescol, Lipitor, Baycol, and Crestor -- 5.5 Zetia and Vytorin -- 6. CNS Drugs -- 6.1 Sternbach, Valium, and Minor Tranquilizers -- 6.2 Antidepressants -- 6.3 Antipsychotics -- 6.4 Drugs for Epilepsy and Bipolar Disorder -- 7. Anti-Inflammatory Drugs -- 7.1 Cortisone -- 7.2 Non-Steroidal Anti-Inflammatory Drags (NSAIDS) -- 7.3 Anti-asthmatics -- 8. Antiulcer Drugs -- 8.1 James Black and the Discovery of Tagamet -- 8.2 Zantac, Pepcid, and Axid -- 8.3 Prilosec and Nexium -- 9. Antiviral Drugs -- 9.1 Influenza Drugs -- 9.2 HIV Drugs -- 9.3 Hepatitis Virus Drugs -- References -- Chapter 2 Target Identification and Validation -- 1. Introduction -- 2 Definition of Drug Targets -- 3 Classification of Currently Utilized Drug Targets -- 4 Receptors as Drug Targets -- 4.1 G-Protein-Coupled Receptors -- 4.2 Ligand-Gated Ion Channels -- 4.3 Receptor Tyrosine Kinases.

4.4 Nuclear Receptors -- 5 Enzymes as Drug Targets -- 6 Transporter Proteins as Drug Targets -- 7 Modern Technologies Employed in Target Identification and Validation -- 7.1 Human Genetics -- 7.2 Gene Family Mining -- 7.3 Gene Expression Profiling in Target Discovery -- 7.4 Proteomics -- 7.5 Oligonucleotides -- 7.6 Model Organisms -- 8 Impact of Therapeutic Modalities on the Selection Drug Targets -- 9 Future Directions -- References -- Chapter 3 In Vitro and In Vivo Assays -- 1 Introduction -- 2 The Testing Funnel -- 3 In Vitro Assays -- 3.1 High-throughput Screening as a Source of Lead Matter -- 3.2 The IC50 as a Measure of Inhibitory Potency -- 3.3 Solubility -- 3.4 Nonspecific (Promiscuous) Inhibitors -- 3.5 Mechanism of Inhibition Studies -- 3.6 How to Identify Allosteric Inhibitors -- 3.7 Selectivity -- 3.8 Tight-binding Inhibition -- 3.9 Slow-Binding Inhibition, Reversibility, and Residence Time -- 3.10 Mechanism, Kinetics, and Potency Comparisons -- 3.11 Cell Assays -- 4 In Vivo Assays -- 4.1 Pharmacokinetics and Pharmacodynamics -- 4.2 Animal Models of Disease -- 4.3 Scaling Up -- 5 Outlook -- References -- Chapter 4 Drug Metabolism and Pharmacokinetics in Drug Discovery -- 1 Introduction -- 2 Drug Metabolism -- 2.1 Drug-Metabolizing Enzymes -- 2.2 In Vitro and In Vivo Models to Evaluate Drug Metabolism -- 2.3 Metabolic Stability -- 2.4 Reaction Phenotyping -- 2.5 Drug-Drug Interactions -- 3 Pharmacokinetic Fundamentals -- 3.1 Noncompartmental Analysis of Pharmacokinetic Data -- 3.2 Compartmental Analysis of Pharmacokinetic Data -- 4 Pharmacokinetic Studies in Support of Drug Optimization -- 5 Absorption and Permeability -- 6 Drug Transporters -- 7 Protein Binding -- 7.1 Protein-Binding Theory -- 7.2 Role of fu in Clearance and Volume of Distribution -- 7.3 Experimental Techniques -- 7.4 Optimization of fu in Drug Discovery.

8 Pharmacokinetics and Pharmacodynamics -- 8.1 Reversible Direct Effects -- 8.2 Time-Delayed Effects -- 9 Predicting Human Pharmacokinetics -- 9.1 Importance of Dose -- 10 Summary -- References -- Chapter 5 Cardiovascular Drugs -- 1 Introduction -- 2 Early History of Coronary Heart Disease (CHD) -- 3 Lipid-Lowering Agents -- 3.1 Nicotinic Acid Derivatives -- 3.2 Bile Acid Sequestrants (BAS) -- 3.3 Fibric acids -- 3.4 Probucol -- 3.5 HMG-CoA Reductase Inhibitors -- 3.6 Cholesterol Absorption Inhibitors -- 3.7 Triglyceride-lowering Agents -- 3.8 HDL-Elevating Agents -- 4 Antihypertensive Agents -- 4.1 Early Vasodilators -- 4.2 Autonomie Nervous System (Sympatholytic) Approaches to Hypertension -- 4.3 Diuretics -- 4.4 Calcium Channel Blockers -- 4.5 The Renin-Angiotensin-Aldosterone System (RAAS) -- 4.6 Endothelin Antagonists -- 5 Antithrombotic Drugs -- 5.1 Antiplatelet Agents -- 5.2 Anticoagulant Agents -- 6 Thrombolytic Agents -- 7 Antianginal Agents -- 8 Heart Failure Drugs -- 9 The Future -- References -- Chapter 6 Diabetes Drugs -- 1 Introduction -- 1.1 Homeostasis of Glucose -- 1.2 Diabetes -- 2 Current therapies for Type 2 Diabetes -- 2.1 Biguanides -- 2.2 Insulin Secretagogues: Sulfonylureas and Glinides -- 2.3 α-Glucosidase Inhibitors -- 2.4 PPARγ Agonists: Thiazolidinediones (TZDs) -- 2.5 Incretin-Based Therapies -- 2.6. Amylin Analog -- 3 Other Treatments for Type 2 Diabetes -- 3.1 Bile Acid Sequestrants -- 3.2 Orlistat -- 3.3 Bromocriptine -- 4 Novel Mechanisms of Action: Future Treatments for Type 2 Diabetes -- 4.1 Sodium-Glucose Co-Transporter 2 (SGLT-2) Inhibitors -- 4.2 PPARs: Next Generation -- 4.3 Glucokinase Activators -- 4.4 GPR119 Agonists -- 4.5 D-Tagatose -- 4.6 11 β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD 1) Inhibitors -- 4.7 Diacylglycerol Acyltransferase 1 (DGAT-1) Inhibitors -- 5 Current Therapies for Type 1 Diabetes.

5.1 Insulin -- 5.2 Insulin Analogs -- 6 Future Treatments for Type 1 Diabetes -- 6.1 Developments in Insulin Area -- 6.2 Approaches to Fight p-cell Destruction -- 7 Future Prospects for New Diabetes Drugs -- References -- Chapter 7 CNS Drugs -- 1. Introduction -- 2. Antipsychotic Drugs -- 2.1 Typical Antipsychotics-The First Generation -- 2.2 Atypical Antipsychotics-The Second Generation -- 2.3 Recent Development of Newer Agents -- 3. Antidepressant Drugs -- 3.1 Monoamine Oxidase Inhibitors (MAOIs) -- 3.2 Tricyclic Antidepressants (TCAs) -- 3.3 Selective Serotonin Reuptake Inhibitors (SSRIs) -- 3.4 Combined Noradrenaline/Serotonin Reuptake Inhibitors (SNRIs) -- 3.5 Novel Approaches -- 4. Drugs for Epilepsy and Bipolar Disorder -- 4.1 Older Antiepileptics -- 4.2 Newer Antiepileptics -- 5. Anxiolytic Drugs -- 5.1 Benzodiazepines -- 5.2 Novel Anxiolytics -- 6. Centrally Acting Analgesic Drugs -- 6.1 Opiates -- 6.2 Miscellaneous CNS Analgesics -- 7. Drugs for treating Substance Abuse and ADHD -- 7.1 Substance Abuse -- 7.2 Attention Deficit Hyperactivity Disorder (ADHD) -- 8. Drugs for Neurodegenerative Diseases -- 8.1 Alzheimer's Disease (AD) -- 8.2 Parkinson's Disease (PD) -- 8.3 Huntington's Disease (HD) -- 8.4 Amyotrophic Lateral Sclerosis (ALS) -- 8.5 New Directions in Neurodegenerative Disease -- 9. Future Prospects for New CNS Drugs -- References -- Chapter 8 Cancer Drugs -- 1 Introduction -- 2 Historical Perspective of Cancer Drugs -- 3 Antimetabolites -- 3.1 Folate Antagonists -- 3.2 Purine and Pyrimidine Antimetabolites -- 4 Alkylating Agents -- 5 Platinum Complexes -- 6 Plant- and Marine-Based Natural Products -- 7 Topoisomerase Inhibitors -- 7.1 Topoisomerase I Inhibitors -- 7.2 Topoisomerase II Inhibitors -- 8 Antitumor Antibiotics -- 9 Tyrosine Kinase Inhibitors (TKIs) -- 9.1 Monoclonal Antibodies -- 10 Hormones -- 10.1 Antiestrogens.

10.2 Androgens -- 10.3 Aromatase Inhibitors -- 10.4 Gonadotropin-Releasing Hormone Agonists -- 10.5 Gonadotropin-Releasing Hormone Antagonists -- 11 Histone Deacetylase (HDAC) Inhibitors -- 12 Miscellaneous Cancer Drugs -- 13 Conclusion -- References -- Chapter 9 Anti-Inflammatory and Immunomodulatory Drugs -- 1 Introduction -- 1.1 Innate Immune Response -- 1.2 Adaptive Immune Response -- 2 Arachidonic Acid Cascade -- 2.1 Cyclooxygenase (COX) Inhibitors -- 2.2 Cyclooxygenase-2 (COX-2) Inhibitors -- 2.3 Prostaglandin I2 (Prostacyclin) -- 2.4 Prostaglandin E2 -- 2.5 Thromboxane A2 -- 3 Leukotriene Pathway Inhibitors -- 3.1 5-Lipoxygenase Inhibitors -- 3.2 Leukotriene Receptor Antagonists -- 4 Antihistamines -- 5 Corticosteroids -- 6 Rheumatoid Arthritis -- 6.1 Methotrexate -- 6.2 Sulfasalazine -- 6.3 Minocycline -- 6.4 Hydroxychloroquine -- 6.5 Leflunomide -- 7 Osteoarthritis -- 8 Chronic Inflammatory Arthritis and Gout -- 8.1 Colchicine -- 8.2 Uricosuric Agents -- 8.3 Xanthine Oxidase -- 8.4 Urate Oxidase -- 9 Multiple Sclerosis -- 9.1 Natalizumab (Tysabri) -- 9.2 IFN-Beta -- 9.3 Mitoxantrone -- 9.4 Glatiramer Acetate (Copaxone) -- 9.5 Fingolimod -- 10 Transplantation -- 10.1 Azathioprine -- 10.2 Cyclosporine -- 10.3 Tacrolimus -- 10.4 Sirolimus (Rapamycin) -- 11 Biological Agents That Suppress Cytokine Production or Signaling -- 11.1 Etanercept -- 11.2 Infliximab -- 11.3 Adalimumab -- 11.4 Golimumab -- 11.5 Certolizumab Pegol -- 12 B-Cell Therapy -- 12.1 Rituximab -- 12.2 Ocrelizumab -- 12.3 Ofatumumab -- 12.4 Belimumab -- 13 Cytotoxic T-Lymphocyte Antigen 4 (CTLA4) -- 13.1 Abatacept -- 13.2 Belatacept -- 14 Interleukins -- 14.1 Tocilizumab -- 14.2 Ustekinumab -- 14.3 Anakinra -- 14.4 Canakinumab -- 14.5 Rilonocept -- 15 Safety -- 16 Summary -- References -- Chapter 10 Antibacterial Drugs -- 1 Introduction -- 2 The Rise and Decline of Antibiotics.

3 The Unique Challenges of Antibacterial Drug Discovery.