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This practice-oriented handbook surveys current knowledge on the prediction and prevention of adverse drug reactions related to off-target activity of small molecule drugs. It is unique in collating the current approaches into a single source, and includes several highly instructive case studies that may be used as guidelines on how to improve drug development projects.With its large section on ADME-related effects, this is key knowledge for every drug developer.
List of contents
PART I: GENERAL ASPECTSWhy drugs fail: study on side effects in New Chemical EntitiesUse of Broad Biological Profiling as a Relevant Descriptor to Describe and Differentiate Compounds: Structure-In Vitro (Pharmacology-ADME)-In Vivo (Safety) RelationshipsPART II: ANTITARGETS: ION CHANNELS AND GPCRsPharmacological and regulatory aspects of QT prolongationhERG Channel Physiology and Drug-Binding Structure-Activity RelationshipsQsar and Pharmacophores for Drugs Involved in hERG BlockageGPCR Antitarget Modeling: Pharmacophore Models to Avoid GPCR-Mediated Side EffectsThe Emergence of Serotonin 5-HT2B Receptors as Drug "Antitargets"Computational Modeling of Selective Pharmacophores at the a1-Adrenergic ReceptorsPART III: ANTITARGETS: CYTOCHROME P450s AND TRANSPORTERSCytochrome P450s: drug-drug interactionsSite of Metabolism Predictions: Facts and ExperiencesIrreversible Cytochrome P450 Inhibition: Common Sub-Structures and Implications for Drug DevelopmentMetaSite: Understanding CYP Antitarget Modeling for Early Toxicity DetectionOrphan Nuclear Receptor PXR-Mediated Gene Regulation in Drug Metabolism and Endobiotic HomeostasisLigand Features Essential for Cytochrome P450 InductionTransporters and Drugs - An OverviewComputational Models for P-Glycoprotein Substrates and InhibitorsPART IV: CASE STUDIES OF DRUG OPTIMIZATION AGAINST ANTITARGETSSelective Dipeptidyl Peptidase IV Inhibitors for the Treatment of Type 2 Diabetes: The Discovery of JANUVIA (Sitagliptin)Strategy and Tactics for hERG OptimizationsStructure-Based In Silico Driven Optimization: Discovery of the Selective 5-HT1A Agonist PRX-00023
About the author
Roy Vaz is the head of investigative pharmacokinetics at the Bridgewater, NJ (USA) location of Sanofi-Aventis Pharmaceuticals. He received his Ph.D. in Organic Chemistry from the University of Florida, Gainesville (USA), after graduating from the Indian Institute of Technology in Mumbai (India). Prior to his present appointment, he has worked with Bristol-Myers-Squibb and Tripos. He is a specialist on the prediction and modeling of cytochrome-mediated drug metabolism.
Thomas Klabunde obtained his PhD in chemistry from the University of Münster (Germany). After a postdoctoral fellowship at the Texas A&M University, he was appointed Assistant Professor at the Institute for Bioscience and Technology in Houston (USA). Later on, he joined the pharmaceutical research of Sanofi-Aventis in Frankfurt (Germany), where he is currently a group leader. His main interest lies with drug design approaches for G protein-coupled receptors, notably in the areas of lead finding and chemogenomics.
Summary
This practice-oriented handbook surveys current knowledge on the prediction and prevention of adverse drug reactions related to off-target activity of small molecule drugs. It is unique in collating the current approaches into a single source, and includes several highly instructive case studies that may be used as guidelines on how to improve drug development projects.
With its large section on ADME-related effects, this is key knowledge for every drug developer.
