Foreword1. Drug Discovery and Development: An Overview of Modern Methods and Principles Drug Discovery and Development from 20,000 FeetTarget Selection: The First Step ForwardHit Identification: Finding a Starting PointIdentify a Clinical Candidate: Juggling the PropertiesQuestionsReferences 2. The Drug Discovery Process: From Ancient Times to the Present Day The Age of Botanicals: Preindustrial Drug DiscoveryPaul Ehrlich: The Father of Modern Drug DiscoveryMilestones in Drug Discovery Milestones in Animal Models: Breeding a Better Model Milestones in Molecular Science X-ray Crystallography Molecular Modeling and Computational Chemistry High Throughput Technology: Chemical Synthesis and Screening Science Milestones in Biotechnology Recombinant DNA and Transfection Technology Polymerase Chain Reaction (PCR) Technology Monoclonal Antibody and Hybridoma TechnologyThe Rise of Biologics and Macromolecular TherapeuticsSocietal and Governmental Impacts The Pure Food and Drug Act of 1906 The Elixir of Sulfanilamide Disaster of 1937 The Thalidomide StoryRegulatory Milestones Durham-Humphrey Amendment of 1951 Kefauver-Harris Amendment of 1962 Hatch-Waxman Act of 1984 Biologics Price Competition and Innovation Act of 2009Future Developments in Drug DiscoveryQuestionsReferences 3. Classical Targets in Drug Discovery Protein StructureEnzymesInhibition of EnzymesG-Protein-Coupled Receptors (GPCRs) G-Protein-Dependent Signaling pathways cAMP Signaling IP3 Signaling Modulating GPCR ActivityIon Channels Gating Mechanisms Ligand-Gated Channels Voltage-Gated Channels Other Gating MechanismsMembrane Transport Proteins (Transporters)Emerging TargetsQuestionsReferences 4. In Vitro Screening Systems The Language of Screening: Basic Terms Concentration Response Curves and IC50s Dissociation Constants (Kd) and Inhibition Constants (Ki) Efficacy versus Binding: EC50s Agonist, Partial Agonist, Antagonist, Allosteric Modulators, and Inverse Agonists Agonists and Partial Agonists Antagonists Basal Activity and Inverse Agonists Allosteric Modulation Receptor ReserveStreptavidin and BiotinBiochemical versus Cellular AssaysAssay Systems and Methods of DetectionRadioligand Systems Scintillation Proximity Assay (SPA)Enzyme-Linked Immunosorbent Assay (ELISA)Fluorescence-Based Assay Systems Fluorescence Polarization (FP) Fluorescence Resonance Energy Transfer (FRET) Time-Resolved Fluorescence Resonance Energy Transfer (TRFRET) Amplified Luminescent Proximity Homogeneous Assay (AlphaScreen(tm)) Fluorescent Detection of Calcium FluxReporter Gene Assays Chloramphenicol Acetyltransferase (CAT) β-Lactamase Reporter Assays Luciferase Reporter AssaysKinetic Fluorescent Measurement SystemsLabel-Free Assay Systems Cellular Dielectric Spectroscopy Optical Biosensors Surface Plasmon Resonance TechnologyElectrophysiological Patch ClampGeneral Consideration for All Screening MethodsQuestionsReferences 5. Medicinal Chemistry Structure-Activity Relationships and Structure-Property RelationshipsThe Role of ChiralityPush and Pull in Structure-Activity RelationshipsQuantitative Structure-Activity RelationshipsThe PharmacophoreDeveloping an SAR Data SetThe Structure-Activity Relationship CycleBioisosterismStructure-Activity Relationship, Selectivity and Physicochemical Properties"Druglike" GuidelinesQuestionsReferences 6. In vitro ADME and In vivo Pharmacokinetics Absorption Solubility PermeabilityDistribution Permeability Transporters Plasma Protein BindingElimination Pathways Metabolism Excretion In vitro ADME Screening Methods In Vivo Pharmacokinetics Volume of Distribution Clearance Half-life BioavailabilitySpecies selectionQuestionsReferences 7. Animal Models of Disease States Sources of Animal ModelsValidity of Animal ModelsSpecies SelectionNumber of AnimalsExemplary Animal Models by Disease Category Animal Models in Neuroscience Animal Models of Neurodegeneration Animal Models of Cardiovascular Disease Models of Hypertension Models of Hyperlipidemia and High Cholesterol Models of Atrial Fibrillation Models of Heart FailureAnimal Models of Infectious Disease Murine Thigh Infection Model Murine Model of Systemic Infection The Mouse Model of Influenza Virus Infection Limitations of Animal Models of InfectionAnimal Models of Oncology Mouse Xenograft Tumor Model Mouse Allograft Tumor Model Genetically Engineered Mouse Models of CancerQuestionsReferences 8.

Safety and Toxicology Sources of ToxicityAcute versus Chronic ToxicityCytotoxicityCarcinogenicity, Genotoxicity, and MutagenicityDrug-Drug InteractionsCardiovascular Safety and Toxicology StudiesCentral Nervous System Safety and Toxicology StudiesImmune System Mediated Safety IssuesTeratogenicity In Vivo Toxicity and Safety StudiesQuestionsReferences 9. Basics of Clinical Trials Before the ClinicDrug SupplyDelivery MethodsFormulationInvestigational New Drug ApplicationPhase I Clinical TrialsPhase II Clinical TrialsPhase III Clinical TrialsPhase IV Clinical TrialsAdaptive Clinical Trial DesignQuestionsReferences 10. Translational Medicine and Biomarkers Definition of a Biomarker and Their ClassificationCharacteristics and Impact of BiomarkersBiomarkers versus Surrogate End PointsImaging TechnologiesThe Practical Application of Biomarkers DPP-IV Inhibitors (Januvia®) Physiological Measurements as Biomarkers: Orexin Antagonists FDG PET Imaging Agent The Neurokinin 1 (NK1) Receptor, Depression, and PET Imaging: The Aprepitant StoryQuestionsReferences 11. Organizational Considerations and Trends in the Pharmaceutical Industry Organizational Structures of Pharmaceutical CompaniesBusiness Divisions InteractionsThe Discovery Project Team Evolutionary CycleThe Business ClimateMergers and AcquisitionsContract Research OrganizationsAcademic Drug DiscoveryFunding IssuesQuestionsReferences 12. Intellectual Property and Patents in Drug Discovery Patentable Subject MatterInherent Properties and PatentabilityNovelty and the Prior ArtObviousness and the Prior ArtInventorshipAssignment and OwnershipClassification of Patents and Patent ApplicationsImpact of Overlapping PatentsPatent Applications and their ContentsContents of a Patent ApplicationQuestionsReferences 13. Case Studies in Drug Discovery Tamiflu: From Mechanism of Action to Marketed DrugHistone Deacylase Inhibitors: Physicochemical Optimization via Structural ChangeHIV Protease Inhibitors: Chemically Complex Miracle DrugsNitrofurantoin: A Surprisingly Successful DrugSeldane® (Terfenadine) versus Allegra® (Fexofenadine): Metabolism Matters: SafetyClaritin® (Loratadine) versus Clarinex® (Desloratadine): Metabolism Matters: PharmacokineticsMPTP: Parkinson''s Disease in a BottleBupropion and Methylphenidate: Improving Performance via Formulation ChangesSelective Inhibition of Cyclooxygenase-2: The Impact of an Inadequate Written DescriptionQuestionsReferences Answers to Questions in Textbook by ChapterSubject IndexDrug Index.