LEADER 05515nam 2200709Ia 450 001 9910877316903321 005 20200520144314.0 010 $a1-282-78430-7 010 $a9786612784309 010 $a3-527-62147-4 010 $a3-527-62146-6 035 $a(CKB)1000000000435481 035 $a(EBL)481424 035 $a(SSID)ssj0000353853 035 $a(PQKBManifestationID)11260956 035 $a(PQKBTitleCode)TC0000353853 035 $a(PQKBWorkID)10302169 035 $a(PQKB)10701433 035 $a(MiAaPQ)EBC481424 035 $a(OCoLC)264389537 035 $a(EXLCZ)991000000000435481 100 $a20070924d2008 uy 0 101 0 $aeng 135 $aur|n|---||||| 181 $ctxt 182 $cc 183 $acr 200 00$aAntitargets $eprediction and prevention of drug side effects /$fedited by Roy J. Vaz and Thomas Klabunde 210 $aWeinheim $cWiley-VCH ;$a[Chichester $cJohn Wiley, distributor]$dc2008 215 $a1 online resource (506 p.) 225 1 $aMethods and principles in medicinal chemistry ;$vv. 38 300 $aDescription based upon print version of record. 311 $a3-527-31821-6 320 $aIncludes bibliographical references and index. 327 $aAntitargets; Contents; List of Contributors; Preface; I General Aspects; 1 Why Drugs Fail - A Study on Side Effects in New Chemical Entities; 1.1 Introduction; 1.2 Drugs Withdrawn from the Market between 1992 and 2006 Listed Alphabetically; 1.2.1 Amineptine; 1.2.2 Aminophenazone (Aminopyrine); 1.2.3 Astemizole; 1.2.4 Bromfenac Sodium; 1.2.5 Cerivastatin; 1.2.6 Chlormezanone; 1.2.7 Fenfluramine and Dexfenfluramine; 1.2.8 Flosequinan; 1.2.9 Glafenine; 1.2.10 Grepafloxacin; 1.2.11 Levacetylmethadol; 1.2.12 Mibefradil; 1.2.13 Rapacuronium Bromide; 1.2.14 Rofecoxib; 1.2.15 Temafloxacin 327 $a1.2.16 Troglitazone1.2.17 Ximelagatran; 1.3 Borderline Cases; 1.4 Investigational Drugs That Failed in Clinical Phases from 1992 to 2002; 1.4.1 A Case Study: Fialuridine; 1.4.2 A Recent Case Study: Torcetrapib; 1.4.3 General Reasons for Project Failing in Clinical Phases I-III; 1.5 Strategies for Avoiding Failure; 1.6 An Unusual Case: The Revival of Thalidomide; References; 2 Use of Broad Biological Profiling as a Relevant Descriptor to Describe and Differentiate Compounds: Structure-In Vitro (Pharmacology-ADME)-In Vivo (Safety) Relationships; 2.1 Introduction 327 $a2.1.1 Biological Profiling/Fingerprints and Drug Discovery Applications2.1.2 Polypharmacology of Drugs; 2.2 The BioPrint(®) Approach; 2.2.1 BioPrint(®) - General; 2.2.2 BioPrint(®) Assay Selection and Profile Description; 2.2.3 Compounds in BioPrint(®); 2.2.4 BioPrint(®) In Vivo Data sets; 2.2.4.1 Compound Details; 2.2.4.2 ADR Data; 2.2.4.3 Pharmacokinetics; 2.2.4.4 Toxicity Data; 2.3 Structure-In Vitro Relationships; 2.3.1 Similarity, Chemotypes - What Is a Biologically Relevant Descriptor?; 2.3.2 Using Biological Fingerprints as a Meaningful Descriptor for Drug Leads and Candidates 327 $a2.3.2.1 Differentiation of Leads2.3.2.2 Analysis of Attrited Compounds; 2.3.3 Structural versus Experimental Differentiation - Dependence on Structure-Derived Descriptor Used; 2.3.4 Predictive Models from Pharmacological Data; 2.3.5 Predictive Models from ADME Data - BioPrint(®) Learnings; 2.4 Chemogenomic Analysis - Target-Target Relationships; 2.5 In Vitro-In Vivo Relationships - Placing Drug Candidates in the Context of BioPrint(®); 2.5.1 Analyzing Potential ADR Liabilities Based on Individual Hits; 2.5.2 Analyzing Potential ADR Liabilities Based on Profile Similarity 327 $a2.6 A Perspective for the FutureReferences; II Antitargets: Ion Channels and GPCRs; 3 Pharmacological and Regulatory Aspects of QT Prolongation; 3.1 Introduction; 3.2 hERG: Target Versus Antitarget; 3.3 Pharmacology of QT Prolongation; 3.3.1 Multiple Mechanisms Leading to QT Prolongation; 3.3.2 hERG as the Key Mechanism for the Drug-Induced Long QT Syndrome; 3.3.3 Pharmacogenetic Aspects; 3.4 Significance of Drug-Induced QT Prolongation; 3.4.1 Prolonged QT/QTc and Occurrence of TdP; 3.4.2 Dose-Response Relationship for QT Prolongation; 3.5 Regulatory Aspects of QT Prolongation 327 $a3.5.1 Regulatory Guidance Documents 330 $aThis practice-oriented handbook surveys current knowledge on the prediction and prevention of adverse drug reactions related to off-target activity of small molecule drugs. It is unique in collating the current approaches into a single source, and includes several highly instructive case studies that may be used as guidelines on how to improve drug development projects.With its large section on ADME-related effects, this is key knowledge for every drug developer. 410 0$aMethods and principles in medicinal chemistry ;$vv. 38. 606 $aDrugs$xSide effects 606 $aDrugs$xSide effects$xPrevention 606 $aDrug interactions 606 $aDrug development 606 $aDrugs$xStructure-activity relationships 615 0$aDrugs$xSide effects. 615 0$aDrugs$xSide effects$xPrevention. 615 0$aDrug interactions. 615 0$aDrug development. 615 0$aDrugs$xStructure-activity relationships. 676 $a615.704 701 $aVaz$b Roy J$01760944 701 $aKlabunde$b Thomas$01760945 801 0$bMiAaPQ 801 1$bMiAaPQ 801 2$bMiAaPQ 906 $aBOOK 912 $a9910877316903321 996 $aAntitargets$94200104 997 $aUNINA