Drug Discovery and Development

ISBN-13: 9781461291800 / Angielski / Miękka / 2011 / 448 str.

Michael Williams; Jeffrey B. Malick; Jeffrey B. Malick

Opis

The conceptual process of drug discovery is one that is often the result of an identified need in a defined disease area. This need represents a mandate from the marketing department of a phar maceutical company or a breakthrough at the research level that has agreed applicability in response to a valid therapeutic demand. Although the intelligent design and development of new thera peutic entities, as evidenced by Sir James Black's H -receptor an 2 tagonist cimetidine (Tagamet), is intellectually satisfying, many novel drugs arise from serendipity, from the chance observation of the research scientist or the clinician, that a compound has unex pected actions of use for the treatment of human disease states. Drugs that have been identified by this route include the antipsy chotic chlorpromazine and the putative anxiolytic buspirone. The events surrounding the process of drug discovery and de velopment are the theme of the present volume, which attempts to present, in a logical and lucid manner, the complexity of a process that is often naively assumed to represent nothing more than the identification of a new compound and its rapid introduction into humans, free of such complications as efficacy, selectivity, safety, bioavailability, toxicity, and need.

Spis treści

Overview.- Drug Discovery and Development: Reflections and Projections.- 1. Introduction.- 2. Drug Discovery.- 2.1. General Issues.- 2.2. Compound Sources.- 2.3. Goal Identification.- 3. The Project Team.- 4. The Flow Chart.- 4.1. The Primary Screen.- 4.2. The Secondary Screen.- 4.3. The Tertiary Screen.- 4.4. Networking.- 4.5. Backup Compounds.- 5. Toxicological Evaluation.- 6. Clinical Evaluation.- 7. Newer Aspects Of Drug Development.- 7.1. The Mechanistic Approach.- 7.2. Drug Delivery.- 8. The Future.- 8.1. The Industry.- 8.2. … and Society.- References.- Compound Discovery.- Drug Design.- 1. Drug Design.- 2. Lead Discovery by Design.- 3. Lead Discovery by Random and Directed Screening.- 4. Quantitative Structure-Activity Relationships.- 5. Pattern Recognition.- 6. Lead Development.- 6.1. Systematic Empirical Approach.- 6.2. Hypothesis-Based Lead Development.- 7. Conclusion.- References.- Computer-Based Approaches to Drug Design.- 1. Introduction.- 2. Theoretical Calculations.- 2.1. Molecular Mechanics-Based Approaches.- 2.2. General Limitations of Theoretical Calculations.- 2.3. Quantum Mechanics-Based Approaches.- 3. Graphical Displays of Molecular Geometry and Steric Volume.- 4. Display of Electronic Properties.- 4.1. Limitations of Partial Charges in Modeling Electronic Interactions.- 4.2. Electrostatic Potential Displays.- 4.3. Qualitative Nature of Electrostatic Potential Displays.- 4.4 Isopotential Surface Displays.- 5. Macromolecular Systems.- References.- Use of Intact Tissue Preparations in the Drug Discovery Process.- 1. Introduction.- 2. General Concepts.- 2.1. Receptors.- 2.2. Dose-Response.- 3. Relevance to Drug Development.- 3.1. Calcium Antagonists.- 3.2. H2 Antagonists.- 3.3. Leukotriene Antagonists.- 4. Summary.- References.- Neuropsychopharmacological Drug Development.- 1. Introduction.- 2. Anxiolytic Drug Discovery and Development.- 2.1. Antianxiety Activity.- 2.2. Anticonvulsant Activity.- 2.3. Muscle Relaxant Potential.- 2.4. Assessment of Sedation and Neuromuscular Impairment.- 2.5. Evaluation of Drug-Interaction Liabilities.- 2.6. Dependence Liability.- 2.7. Behavioral Assessment of Benzodiazepine Antagonist Activity.- 2.8. Behavioral Differentiation of Benzodiazepine Displacer and Nondisplacer Anxiolytics.- 2.9. Potential False Positives.- 3. Summary.- References.- Biochemical Approaches for Evaluating Drug—Receptor Interactions.- 1. Introduction.- 2. Neurotransmitter Receptor Binding.- 2.1. Criteria for Identification of a Receptor Binding Site.- 2.2. Analysis of Binding Data.- 2.3. Drug—Binding Site Interactions.- 3. Receptor-Mediated Responses.- 3.1. Cyclic AMP.- 3.2. Phosphatidylinositol Metabolism.- 4. Drug Screening.- References.- Drug Discovery at the Enzyme Level.- 1. Introduction.- 2. Enzyme Assays In Vitro.- 2.1. Detecting Substrate Disappearance or Product Formation.- 2.2. Reaction Conditions.- 3. Sources of Inhibitors.- 3.1. Chemical Synthesis.- 3.2. Natural Products.- 4. Characterization of Inhibitors In Vitro.- 4.1. Reversible or Irreversible.- 4.2. Competitive, Noncompetitive, or Uncompetitive Inhibitors.- 4.3. Specificity.- 5. Demonstration of Enzyme Inhibition In Vivo.- 5.1. Ex Vivo Inhibition.- 5.2. Substrate Conversion In Vivo.- 5.3. Antagonism of Mechanism-Based Inactivation.- 5.4. Substrate Accumulation or Product Depletion.- 5.5. Functional Effects.- 6. Specific Examples of Enzyme Inhibitors Used as Drugs.- 6.1. Monoamine Oxidase Inhibitors.- 6.2. Xanthine Oxidase Inhibitors.- 6.3. Carbidopa.- 7. Summary.- References.- EEG, EEG Power Spectra, and Behavioral Correlates of Opioids and Other Psychoactive Agents.- 1. Electroencephalography (EEG) — An Overview.- 2. Use of EEG and EEG Power Spectra in Drug Classification.- 2.1. Clinical Use of EEG Quantification in the Study of Psychoactive Drugs.- 2.2. Pharmaco-EEG Correlates of Psychoactive Agents in Experimental Animals.- 3. Delineation of Opioid Pharmacodynamic Properties with EEG and Behavior.- 3.1. Introduction.- 3.2. Differential Effects of Mu, Kappa, and Sigma Agonists on EEG, EEG Power Spectra, and Behavior.- 3.3. Tolerance and Cross-Tolerance Among Opioids.- 3.4. Differential Abstinence Syndromes Between Rats Chronically Treated with Mu and Kappa Opioid Agonists.- 3.5. Characteristic Changes in REM Sleep EEG Frequencies During Opioid Self-Administration.- 4. Pharmacodynamics of Other Psychotropic Drugs.- 4.1. EEG and Behavioral Effects of Ethanol.- 4.2. EEG and Behavioral Effects of Cannabinoids.- 5. Use of EEG Power Spectra in Neurotoxicology Studies.- 6. Summary and Conclusions.- References.- Immunopharmacological Approaches to Drug Development.- 1. Introduction.- 2. The Immune System.- 2.1. Anatomy.- 2.2. Cellular Components and Their Functions.- 2.3. Role of Cytokines in Immunity.- 3. Potential Therapeutic Targets for Immunomodulatory Drugs.- 3.1. Immunodeficiency Diseases.- 3.2. Autoimmune Diseases.- 3.3. Allergic Disorders.- 4. Immunomodulatory Agents.- 4.1. General Considerations.- 4.2. Classification.- 4.3. Biological Testing Procedures for Identifying Immunomodulatory Drugs.- 4.4. Immunomodulatory Agents in Current Use or Under Development.- 5. New Approaches Under Development.- 5.1. Monoclonal Antibodies.- 5.2. Cytokines.- 6. Summary.- References.- Toxicological Evaluation and Clinical Aspects.- Toxicological Evaluation of Drugs.- 1. Introduction.- 1.1. The Drug.- 1.2. The Test System.- 1.3. The Regimens.- 2. Toxicity Data Requirements.- 2.1. Acute Toxicity Studies.- 2.2. Subacute or Subchronic Toxicity (Short-Term Studies).- 2.3. Chronic Toxicity (Long-Term Studies).- 2.4. Carcinogenicity.- 2.5. Mutagenicity Studies.- 2.6. Reproduction and Teratology Studies.- 2.7. Metabolism Studies.- 2.8. Immunotoxicity Studies.- 2.9. Behavioral Toxicity Studies.- 3. Alternatives to Animal Testing.- 3.1. Short-Term In Vivo Studies.- 3.2. In Vitro Studies.- 3.3. Structure-Activity Models.- 4. Good Laboratory Practices.- 5. Future Trends in Toxicity Studies — “The Age of Biotoxicology”.- References.- Drug Delivery Systems.- 1. Introduction.- 2. Rationale for Selecting a Drug Delivery System.- 2.1. Terminology.- 3. Matrix Control of Drug Release.- 3.1. Theory.- 3.2. Oral Matrix Release Systems.- 3.3 Matrix Implants.- 3.4. Vaginal Inserts.- 3.5. Intrauterine Devices.- 3.6. Matrix Transdermal Delivery.- 3.7. Slow-Release Pesticide Generators.- 3.8. Nanoparticles.- 4. Membrane Control of Drug Release.- 4.1. Theory.- 4.2. Oral Dosage Forms.- 4.3. Ocular Systems.- 4.4. Transdermal Systems.- 4.5. Pesticide Generators.- 5. Ion Exchange.- 6. Biodegradable Polymers.- 6.1. Chemical Biodegradation — Matrix Release.- 6.2. Biodegradable Drug Carrier Complexes.- 7. Cellular Methods.- 7.1. Artificial/Naturally Occurring Cellular Methods.- 7.2. Liposomes.- 8. Mechanical Pumps.- 9. Conclusions.- References.- Clinical Evaluation of Drug Candidates.- 1. Introduction.- 2. Requirements and Timing for Proceeding to Human Trials.- 3. Definition and Scope of the Phases of Drug Development.- 3.1. Phase I.- 3.2. Phase II.- 3.3. Phase III.- 3.4. Phase IV.- 3.5. Phase V.- 4. Clinical Assessment of Safety.- 5. Assessment of Efficacy.- 6. Clinical Trial Methodology.- 6.1. Study Design.- 6.2. Randomization.- 6.3. Study Duration and Schedule of Observations.- 6.4. Patient Selection.- 6.5. Number of Subjects (Sample Size).- 6.6. Case Report Forms.- 6.7. Conduct and Monitoring of Clinical Trials.- 7. Ethical and Legal Considerations.- 8. New Drug Registration.- 8.1. Preparation of the New Drug Application in the US.- 8.2. NDA Review in the US.- 8.3. International Drug Registration.- References.- Therapeutic Entities—From Discovery to Human Use.- Cimetidine and Other Histamine H2-Receptor Antagonists.- 1. Peptic Ulcer Disease.- 2. Chemical Messengers and the Search for New Antiulcer Drugs.- 3. Pharmacological Characterization of Histamine Receptors.- 4. Discovery of H2-Receptor Antagonists.- 4.1. Background to Cimetidine.- 4.2. Development of Newer H2-Receptor Antagonists.- 5. Toxicology of Burimamide, Metiamide, and Cimetidine and More Recently Developed H2-Receptor Antagonists.- 6. Safety and Efficacy of Cimetidine in Widespread Clinical Use.- 7. Therapeutic Use of H2-Receptor Antagonists — Lessons Learned.- 8. Therapeutic Use of H2-Receptor Antagonists in Indications Unrelated to Hypersecretion of Gastric Acid.- References.- Atypical Psychotropic Agents: Trazodone and Buspirone.- 1. Introduction: Identifying Atypical Agents.- 2. Antidepressants.- 2.1. An Atypical Antidepressant: Trazodone.- 2.2. Discovery and Development of Nefazodone.- 3. Anxiolytics.- 3.1. Discovery and Development of Buspirone.- 3.2. Novel Mechanisms of Action.- 3.3. Second-Generation Compounds: Gepirone.- 4. Conclusions.- References.- Calcium Channel Antagonists.- 1. Introduction.- 1.1. Calcium and Cellular Function.- 1.2. Therapeutic Utility of Blocking Calcium Entry.- 2. Discovery and Physiological Effects of Calcium Channel Blockers.- 2.1. Historical Perspective.- 2.2. Physiological Effects.- 3. Biochemical Characterization.- 3.1. 3H-Dihydropyridines and Novel Antagonists.- 3.2. 3H-Phenylalkylamines.- 3.3. 3H-Diltiazem.- 4. Summary.- References.