Analogue-Based Drug Discovery III

389 Pages·2012·4.902 MB·English

EditedbyJ(cid:1)anosFischer,
C.RobinGanellinand
DavidP.Rotella
Analogue-basedDrugDiscoveryIII
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Edited by Janos Fischer, C. Robin Ganellin
and David P. Rotella
Analogue-based Drug Discovery III
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V
Contents
Preface XIII
ListofContributors XV
PartI GeneralAspects 1
1 PioneerandAnalogueDrugs 3
J(cid:1)anosFischer,C.RobinGanellin,andDavidP.Rotella
1.1 MonotargetDrugs 5
1.1.1 H ReceptorHistamineAntagonists 5
2
1.1.2 ACEInhibitors 6
1.1.3 DPPIVInhibitors 7
1.1.4 UnivalentDirectThrombinInhibitors 8
1.2 Dual-ActingDrugs 10
1.2.1 MonotargetDrugsfromDual-ActingDrugs 10
1.2.1.1 OptimizationofBeta-AdrenergicReceptorBlockers 10
1.2.2 Dual-ActingDrugsfromMonotargetDrugs 11
1.2.2.1 Dual-ActingOpioidDrugs 11
1.3 MultitargetDrugs 12
1.3.1 MultitargetDrugAnaloguetoEliminateaSideEffect 12
1.3.1.1 ClozapineandOlanzapine 12
1.3.2 SelectiveDrugAnaloguefromaPioneerMultitargetDrug 13
1.3.2.1 SelectiveSerotoninReuptakeInhibitors 13
1.4 Summary 16
Acknowledgments 16
References 16
2 CompetitioninthePharmaceuticalDrugDevelopment 21
ChristianTyrchanandFabrizioGiordanetto
2.1 Introduction 21
2.2 Analogue-BasedDrugs:JustCopies? 22
j
VI Contents
2.3 HowOftenDoesAnalogue-BasedActivityOccur?Insightsfromthe
GPCRPatentSpace 25
References 32
3 MetabolicStabilityandAnalogue-BasedDrugDiscovery 37
AmitS.KalgutkarandAntoniaF.Stepan
ListofAbbreviations 37
3.1 Introduction 37
3.2 Metabolism-GuidedDrugDesign 39
3.3 IndirectModulationofMetabolismbyFluorineSubstitution 42
3.4 ModulationofLowClearance/LongHalf-LifeviaMetabolism-Guided
Design 45
3.5 TacticstoResolveMetabolismLiabilitiesDuetoNon-CYPEnzymes 46
3.5.1 AldehydeOxidase 46
3.5.2 MonoamineOxidases 48
3.5.3 PhaseIIConjugatingEnzymes(UGTandSulfotransferases) 49
3.6 EliminatingRMLiabilitiesinDrugDesign 51
3.7 EliminatingMetabolism-DependentMutagenicity 51
3.8 EliminatingMechanism-BasedInactivationofCYPEnzymes 54
3.9 Identification(andElimination)ofElectrophilicLeadChemical
Matter 60
3.10 MitigatingRisksofIdiosyncraticToxicityviaEliminationofRM
Formation 61
3.11 CaseStudiesonEliminationofRMLiabilityinDrugDiscovery 62
3.12 ConcludingRemarks 67
References 68
4 UseofMacrocyclesinDrugDesignExemplifiedwithUlimorelin,
aPotentialGhrelinAgonistforGastrointestinalMotilityDisorders 77
(cid:1)
MarkL.Peterson,HamidHoveyda,GraemeFraser,EricMarsault,
andRen(cid:1)eGagnon
4.1 Introduction 77
4.1.1 GhrelinasaNovelPharmacologicalTargetforGIMotility
Disorders 77
4.1.2 MacrocyclesinDrugDiscovery 79
4.1.3 TranzymeTechnology 80
4.2 High-ThroughputScreeningResultsand
HitSelection 82
4.3 MacrocycleStructure–ActivityRelationships 83
4.3.1 PreliminarySAR 83
4.3.2 RingSizeandTether 83
4.3.3 AminoAcidComponents 87
4.3.4 FurtherTetherOptimization 89
4.4 PK–ADMEConsiderations 92
4.5 StructuralStudies 95
4.6 PreclinicalEvaluation 96
j
Contents VII
4.6.1 AdditionalCompoundProfiling 97
4.6.2 AdditionalPharmacokineticData 98
4.6.3 AnimalModelsforPreclinicalEfficacy 100
4.7 ClinicalResultsandCurrentStatus 100
4.8 Summary 103
References 104
PartII DrugClasses 111
5 TheDiscoveryofAnticancerDrugsTargetingEpigeneticEnzymes 113
A.Ganesan
ListofAbbreviations 113
5.1 Epigenetics 114
5.2 DNAMethyltransferases 116
5.3 5-Azacytidine(Azacitidine,Vidaza)and5-Aza-20-deoxycytidine
(Decitabine,Dacogen) 118
5.4 OtherNucleosideDNMTInhibitors 122
5.5 PreclinicalDNMTInhibitors 123
5.6 Zinc-DependentHistoneDeacetylases 124
5.7 SuberoylanilideHydroxamicAcid(SAHA,Vorinostat,Zolinza) 125
5.8 FK228(Depsipeptide,Romidepsin,Istodax) 127
5.9 CarboxylicAcidandBenzamideHDACInhibitors 131
5.10 ProspectsforHDACInhibitors 132
5.11 EpigeneticDrugs–ASlowStartbutaBrightFuture 133
Acknowledgments 133
References 134
6 ThienopyridylandDirect-ActingP2Y ReceptorAntagonistAntiplatelet
12
Drugs 141
JosephA.JakubowskiandAtsuhiroSugidachi
ListofAbbreviations 141
6.1 Introduction 142
6.1.1 PlateletInvolvementinAtherothrombosis 142
6.2 Thienopyridines 143
6.2.1 Ticlopidine:5-[(2-Chlorophenyl)methyl)-4,5,6,7-tetrahydrothieno[3,2-c]
pyridine 144
6.2.2 Clopidogrel:(þ)-(S)-a-(2-Chlorophenyl)-6,7-dihydrothieno[3,2-c]
pyridine-5(4H)acetate 145
6.2.3 Prasugrel:5-[(1RS)-2-Cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-
tetrahydrothieno[3,2-c]pyridin-2-ylacetate 147
6.3 Direct-ActingP2Y Antagonists 152
12
6.3.1 Nucleoside-ContainingAntagonists 152
6.3.1.1 Cangrelor:[Dichloro-[[[(2R,3S,4R,5R)-3,4-dihydroxy-5-[6-(2-
methylsulfanylethylamino)-2-(3,3,3-trifluoropropylsulfanyl)purin-9-yl]
oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl]methyl]
phosphonicacid 153
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VIII Contents
6.3.1.2 Ticagrelor:(1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-Difluorophenyl)
cyclopropylamino]-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-
3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol 154
6.3.2 Non-NucleosideP2Y Antagonists 157
12
6.3.2.1 Elinogrel:N-[(5-Chlorothiophen-2-yl)sulfonyl]-N0-{4-[6-fluoro-
7-(methylamino)-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl]phenyl}
urea 157
6.4 Summary 158
References 158
7 SelectiveEstrogenReceptorModulators 165
AmarjitLuniwal,RachaelJetson,andPaulErhardt
ListofAbbreviations 165
7.1 Introduction 166
7.1.1 WorkingDefinition 166
7.1.2 EarlyABDDLeadingtoaPioneerSERM 167
7.1.3 DiscoveryandDevelopmentofClomiphene 169
7.1.4 SERM-DirectedABDD:GeneralConsiderations 170
7.2 Tamoxifen 171
7.2.1 EarlyDevelopment 171
7.2.2 ClinicalIndicationsandMolecularAction 172
7.2.3 PharmacokineticsandMajorMetabolicPathways 174
7.2.4 ClinicalToxicityandNewTamoxifenAnalogues 175
7.3 Raloxifene 175
7.3.1 NeedforNewAntiestrogens 176
7.3.2 DesignandInitialBiologicalDataonRaloxifene 176
7.3.3 RUTHStudy 177
7.3.4 STARStudy 177
7.3.5 BindingtotheEstrogenReceptor 178
7.3.6 ADME 179
7.3.7 FurtherResearch 179
7.4 Summary 179
References 180
8 DiscoveryofNonpeptideVasopressinV2ReceptorAntagonists 187
KazumiKondoandHidenoriOgawa
ListofAbbreviations 187
8.1 Introduction 187
8.2 PeptideAVPAgonistsandAntagonists 188
8.3 LeadGenerationStrategies 189
8.4 LeadGenerationStrategy-2,V ReceptorAffinity 192
2
8.5 LeadOptimization 197
8.6 ReportedNonpeptideVasopressinV ReceptorAntagonist
2
Compounds 199
8.6.1 Sanofi 199
j
Contents IX
8.6.2 Astellas(Yamanouchi) 199
8.6.3 Wyeth 201
8.6.4 Johnson&Johnson 201
8.6.5 WakamotoPharmaceuticalCo.Ltd 202
8.6.6 JapanTobaccoInc. 202
8.7 Conclusions 203
References 203
9 TheDevelopmentofCysteinylLeukotrieneReceptorAntagonists 211
PeterR.Bernstein
ListofAbbreviations 211
9.1 Introduction 212
9.2 ScopeoftheDrugDiscoveryEffortonLeukotrieneModulators 214
9.3 SyntheticLeukotrieneProductionandBenefitsDerivedfromthis
Effort 215
9.4 BioassaysandGeneralDrugDiscoveryTestingCascade 216
9.5 DevelopmentofAntagonists–GeneralApproaches 218
9.6 DiscoveryofZafirlukast 218
9.7 DiscoveryofMontelukast 224
9.8 DiscoveryofPranlukast 227
9.9 ComparativeAnalysisandCrossoverImpact 229
9.10 PostmarketingIssues 231
9.11 Conclusions 232
Acknowledgment 232
Disclaimer 232
References 233
PartIII CaseStudies 241
10 TheDiscoveryofDabigatranEtexilate 243
NorbertHauel,AndreasClemens,HerbertNar,HenningPriepke,
JoannevanRyn,andWolfgangWienen
ListofAbbreviations 243
10.1 Introduction 243
10.2 DabigatranDesignStory 246
10.3 PreclinicalPharmacologyMolecularMechanismofActionof
Dabigatran 254
10.3.1 InVitroAntihemostaticEffectsofDabigatran 255
10.3.2 ExVivoAntihemostaticEffectsofDabigatran/DabigatranEtexilate 256
10.3.3 VenousandArterialAntithromboticEffectsofDabigatran/Dabigatran
Etexilate 256
10.3.4 MechanicalHeartValves 257
10.3.5 Cancer 257
10.3.6 Fibrosis 257
10.3.7 Atherosclerosis 258
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X Contents
10.4 ClinicalStudiesandIndications 258
10.4.1 PreventionofDeepVenousThrombosis 259
10.4.2 TherapyofVenousThromboembolism 259
10.4.3 StrokePreventioninPatientswithAtrialFibrillation 260
10.4.4 PreventionofRecurrentMyocardialInfarctioninPatientswithAcute
CoronarySyndrome 260
10.5 Summary 260
References 261
11 TheDiscoveryofCitalopramandItsRefinementtoEscitalopram 269
KlausP.BøgesøandConnieS(cid:1)anchez
ListofAbbreviations 269
11.1 Introduction 270
11.2 DiscoveryofTalopram 271
11.3 DiscoveryofCitalopram 272
11.4 SynthesisandProductionofCitalopram 275
11.5 ThePharmacologicalProfileofCitalopram 276
11.6 ClinicalEfficacyofCitalopram 277
11.7 SynthesisandProductionofEscitalopram 278
11.8 ThePharmacologicalProfileoftheCitalopramEnantiomers 279
11.9 R-Citalopram’sSurprisingInhibitionofEscitalopram 279
11.10 BindingSite(s)forEscitalopramontheSerotoninTransporter 283
11.11 FuturePerspectivesontheMolecularBasisforEscitalopram’s
InteractionwiththeSERT 286
11.12 ClinicalEfficacyofEscitalopram 287
11.13 Conclusions 288
References 288
12 Tapentadol–FromMorphineandTramadoltotheDiscovery
ofTapentadol 295
HelmutBuschmann
ListofAbbreviations 295
12.1 Introduction 296
12.1.1 PainandCurrentPainTreatmentOptions 297
12.1.2 PainResearchToday 300
12.1.3 TheComplexModeofActionofTramadol 301
12.2 TheDiscoveryofTapentadol 302
12.2.1 FromtheTramadolStructuretoTapentadol 303
12.2.2 SyntheticPathwaystoTapentadol 306
12.3 ThePreclinicalandClinicalProfileofTapentadol 310
12.3.1 PreclinicalPharmacologyofTapentadol 311
12.3.2 ClinicalTrials 312
12.3.3 PharmacokineticsandDrug–DrugInteractionsofTapentadol 314
12.4 Summary 315
References 315