Reactive Drug Metabolites

ALERTSIntroductionIntrinsically Reactive ToxicophoresToxicophores that Require Bioactivation to Reactive MetabolitesConcluding RemarksINTRINSICALLY ELECTROPHILIC COMPOUNDS AS A LIABILITY IN DRUG DISCOVERYIntroductionIntrinsic Electrophilicity of b-Lactam Antibiotics as a Causative Factor in ToxicityIntrinsically Electrophilic Compounds in Drug DiscoverySerendipitous Identification of Intrinsically Electrophilic Compounds in Drug DiscoveryROLE OF REACTIVE METABOLITES IN PHARMACOLOGICAL ACTIONIntroductionDrugs Activated Nonenzymatically and by Oxidative MetabolismBioreductive Activation of DrugsConcluding RemarksRETROSPECTIVE ANALYSIS OF STRUCTURE - TOXICITY RELATIONSHIPS OF DRUGSIntroductionIrreversible Secondary PharmacologyPrimary Pharmacology and Irreversible Secondary PharmacologyPrimary or Secondary Pharmacology and Reactive Metabolites: the Possibility for False Structure - Toxicity RelationshipsMultifactorial Mechanisms as Causes of ToxicityClear Correlation between Protein Target and Reactive MetabolitesConclusion - Validation of Reactive Metabolites as Causes of ToxicityBIOACTIVATION AND NATURAL PRODUCTSIntroductionWell-Known Examples of Bioactivation of Compounds Present in Herbal RemediesWell-Known Examples of Bioactivation of Compounds Present inFoodsSummaryEXPERIMENTAL APPROACHES TO REACTIVE METABOLITE DETECTIONIntroductionIdentification of Structural Alerts and avoiding them in Drug DesignAssays for the Detection of Reactive MetabolitesOther Studies that can Show the Existence of Reactive MetabolitesConclusionCASE STUDIES ON ELIMINATING/REDUCING REACTIVE METABOLITE FORMATION IN DRUG DISCOVERYMedicinal Chemistry Tactics to Eliminate Reactive Metabolite FormationEliminating Reactive Metabolite Formation on Heterocyclic Ring SystemsMedicinal Chemistry Strategies to Mitigate Bioactivation of Electron-Rich Aromatic RingsMedicinal Chemistry Strategies to Mitigate Bioactivation on a Piperazine Ring SystemConcluding RemarksSTRUCTURAL ALERT AND REACTIVE METABOLITE ANALYSIS FOR THE TOP 200 DRUGS IN THE US MARKET BY PRESCRIPTIONIntroductionStructural Alert and Reactive Metabolite Analyses for the Top 20 Most Prescribed Drugs in the United States for the Year 2009Insights into the Excellent Safety Records for Reactive Metabolite - Positive Blockbuster DrugsStructural Alert and Reactive Metabolite Analyses for the Remaining 180 Most Prescribed DrugsStructure Toxicity TrendsMITIGATING TOXICITY RISKS WITH AFFINITY LABELING DRUG CANDIDATESIntroductionDesigning Covalent InhibitorsOptimization of Chemical Reactivity of the Warhead MoietyConcluding RemarksDEALING WITH REACTIVE METABOLITE - POSITIVE COMPOUNDS IN DRUG DISCOVERYIntroductionAvoiding the Use of Structural Alerts in Drug DesignStructural Alert and Reactive Metabolite FormationShould Reactive Metabolite - Positive Compounds be nominated as Drug Candidates?The Multifactorial Nature of IADRsConcluding RemarksMANAGING IADRS ' A RISK' BENEFIT ANALYSISRisk - Benefit AnalysisHow common is Clinical Drug Toxicity?Rules and Laws of Drug ToxicityDifficulties in Defining Cause and Black Box WarningsLabeling Changes, Contraindications, and Warnings: the Effectiveness of Side Effect MonitoringAllele Association with Hypersensitivity Induced by Abacavir: Toward a Biomarker for ToxicityMore Questions than Answers: Benefit Risk for ADRsINDEX

advisory capacity. He has authored over 130 publications including three books.