Antiviral Drug Strategies (Methods and Principles in Medicinal Chemistry, Volume 50)

427 Pages·2011·4.12 MB·English

by  Erik De Clercq

Edited by
Erik De Clercq
Antiviral Drug Strategies
Methods and Principles in Medicinal Chemistry
Editedby R. Mannhold,H.Kubinyi, G.Folkers
EditorialBoard
H.Buschmann, H.Timmerman, H.van de Waterbeemd, T.Wieland
Previous Volumes of this Series:
Klebl,Bert/Müller,Gerhard/Hamacher, Ecker, GerhardF. /Chiba,Peter (Eds.)
Michael (Eds.) Transporters as Drug Carriers
Protein Kinases as Drug
Structure,Function,Substrates
Targets 2009
2011 ISBN:978-3-527-31661-8
Vol.44
ISBN:978-3-527-31790-5
Vol.49 Faller,Bernhard /Urban,Laszlo(Eds.)
Hit and Lead Profiling
Sotriffer,Christopher (Ed.)
Virtual Screening IdentificationandOptimization
ofDrug-likeMolecules
Principles,Challenges,and
2009
PracticalGuidelines
ISBN:978-3-527-32331-9
2011
Vol.43
ISBN:978-3-527-32636-5
Vol.48 Sippl, Wolfgang/Jung,Manfred (Eds.)
Epigenetic Targets in Drug
Rautio,Jarkko (Ed.)
Discovery
Prodrugs and Targeted
Delivery 2009
ISBN:978-3-527-32355-5
TowardsBetterADMEProperties
Vol.42
2011
Todeschini,Roberto/Consonni,Viviana
ISBN:978-3-527-32603-7
Vol.47 Molecular Descriptors for
Chemoinformatics
Smit,Martine J./Lira,Sergio A./
Leurs, Rob(Eds.) VolumeI:AlphabeticalListing/
VolumeII:Appendices,References
Chemokine Receptors
2009
as Drug Targets
ISBN:978-3-527-31852-0
2011
Vol.41
ISBN:978-3-527-32118-6
van deWaterbeemd, Han/
Vol.46
Testa,Bernard (Eds.)
Ghosh, Arun K.(Ed.) Drug Bioavailability
Aspartic Acid Proteases
Estimation of Solubility, Permeability,
as Therapeutic Targets AbsorptionandBioavailability
2010 Second,CompletelyRevisedEdition
ISBN:978-3-527-31811-7 2008
Vol.45 ISBN:978-3-527-32051-6
Vol.40
Edited by
Erik De Clercq
Antiviral Drug Strategies
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V
Contents
List of Contributors XIII
Preface XVII
A Personal Foreword XIX
1 OutlookoftheAntiviralDrugEra,NowMoreThan50YearsAfter
DescriptionoftheFirstAntiviralDrug 1
ErikDeClercq
1.1 Introduction:ThePrehistory 1
1.2 KeyEventsinAntiviralDrugDevelopment 2
1.3 AntiviralDrugs:CurrentStateoftheArt 4
1.4 AntiviralDrugsActiveagainstHerpesviruses
(i.e.,HSV,VZV,andsoon) 4
1.5 AntiviralDrugsActiveagainstRetroviruses(HIV) 8
1.6 AntiviralDrugsActiveagainstHepatitisBVirus 12
1.7 AntiviralDrugsActiveagainstDNAVirusesatLarge 13
1.8 AntiviralDrugsforInfluenzaAVirusInfections 14
1.9 AntiviralDrugsforHepatitisCVirus 15
1.10 AntiviralDrugsforPoxviruses(i.e.,Variola,
Vaccinia,andsoon) 17
1.11 FurtherOptionstoTreatVirusInfections 19
1.12 Conclusions 19
References 20
2 InhibitionofHIVEntry 29
JoséA.Esté
2.1 Introduction 29
2.2 TheHIVGlycoproteins 30
2.2.1 StructureoftheHIV-1Glycoproteingp120 30
2.2.2 StructureoftheHIV-1TransmembraneGlycoproteingp41 31
2.3 MechanismofHIVEntry 32
2.3.1 VirusAttachment 32
2.3.2 Coreceptors:VirusTropismandInfectivity 33
VI Contents
2.3.3 Virus–CellFusion 33
2.3.4 EndocytosisofHIV 33
2.4 InhibitionofHIVEntry 34
2.4.1 InhibitorsofVirusAttachment 34
2.4.1.1 PolyanionsasInhibitorsofHIVAttachment 34
2.4.1.2 Small-MoleculeInhibitorsofthegp120–CD4Interaction 36
2.4.2 PostattachmentInhibitors 37
2.4.3 CCR5Antagonists 38
2.4.3.1 Maraviroc 38
2.4.3.2 Vicriviroc 39
2.4.3.3 Pro-140 39
2.4.3.4 ResistancetoCCR5Antagonists 39
2.4.4 CXCR4Antagonists 40
2.4.5 InhibitorsofHIVFusion:Enfuvirtide 41
2.5 ConcludingRemarks 42
References 42
3 TargetingIntegrationBeyondStrandTransfer:Development
ofSecond-GenerationHIVIntegraseInhibitors 51
ArnoutR.D.Voet,MarcDeMaeyer,FraukeChrist,andZegerDebyser
3.1 HIV:TheCausativeAgentofAIDS 51
3.1.1 ReplicationCycleofHIV 51
3.1.2 HighlyActiveAntiretroviralTherapy 52
3.2 TheIntegrationStep:AComplexMechanismwithDifferent
PossibilitiesforInhibition 53
3.2.1 HIV-1Integrase 53
3.2.1.1 TheStructuralOrganizationofHIV-1Integrase 54
3.2.2 HIV-1INasaTargetforHAART 55
3.2.2.1 IntegraseStrandTransferInhibitors 55
3.2.2.2 IntegraseBindingInhibitors 57
3.3 DNABindingInhibitors 59
3.4 MultimerizationInhibitors 60
3.5 TargetingIntegraseCofactorInteractions 62
3.6 Conclusion 64
References 65
4 FromSaquinavirtoDarunavir:TheImpactof
10YearsofMedicinalChemistryonaLethalDisease 73
Marie-PierredeBéthune,AnikPeeters,andPietWigerinck
4.1 Introduction 73
4.2 TheHIVProteaseasaTargetforAIDS 73
4.3 TheEarlyProteaseInhibitors 74
4.4 TheMedicalNeedfora‘‘Next’’-GenerationPI 78
4.5 HowCanWeExplaintheSuperiorAntiviralActivity
ofDarunavir? 85
Contents VII
4.6 ClinicalDevelopmentofDarunavir 86
4.7 ConclusionsandFutureDevelopments 87
References 87
5 AcyclicandCyclicNucleosidePhosphonates 91
RichardL.MackmanandTomasCihlar 91
5.1 Introduction 91
5.2 NucleosidePhosphonateStrategyforAntivirals 92
5.3 AcyclicNucleosidePhosphonates 95
5.3.1 MainClassesandtheirStructure–ActivityRelationships 95
5.3.1.1 HPMPAnalogues 95
5.3.1.2 PMEAnalogues 95
5.3.1.3 PMPandFPMPAnalogues 97
5.3.2 AdditionalExamplesofAntiviralANPs 98
5.4 CyclicNucleosidePhosphonates 99
5.4.1 MainClassesandtheirStructure–ActivityRelationships 100
5.4.1.1 TetrahydrofuranCore 100
5.4.1.2 CyclopentaneandCyclopenteneCores 103
5.4.2 ExamplesofCNPsTargetingViralRNAPolymerases 104
5.5 ProdrugsofNucleosidePhosphonates 107
5.5.1 Phosphonoesters 107
5.5.2 Phosphonoamidates 109
5.6 ClinicalApplicationsofAntiviralNucleosidePhosphonates 111
1
5.6.1 Cidofovir(Vistide ) 112
1
5.6.2 AdefovirDipivoxil(Hepsera ) 112
1
5.6.3 TenofovirDisoproxilFumarate(Viread ) 113
5.7 Conclusions 115
References 115
6 Helicase–PrimaseInhibitors:ANewApproachtoCombat
HerpesSimplexVirusandVaricellaZosterVirus 129
SubhajitBiswasandHughJ.Field
6.1 Introduction 129
6.2 TheRoleofHelicasePrimaseintheReplicationofHSV 130
6.3 SelectiveInhibitorsofHelicasePrimaseasAntiherpesvirus
Antivirals 131
6.4 HPIsareEffectiveinCellCultureandInVivo 133
6.5 EffectsofHPIsontheEstablishmentandReactivation
fromLatency 134
6.6 HPIs:TheBiochemicalBasisfortheProposedMechanism
ofAction 134
6.7 HSVAcquiredResistancetoHPIs 135
6.8 PatternsofCross-Resistance 136
6.9 FurtherInsightintoModeofHPIInteractionwiththeHSVHP
ComplexfromtheStudyofResistanceMutations 139
VIII Contents
6.10 TheFrequencyandOriginofHPI-ResistanceMutations 140
6.11 UL5Lys356Asn:aMutationConferringHighResistancetoHPI 141
6.12 TheOriginofResistanceMutationsatHighFrequency 142
6.13 Conclusions 142
References 144
7 CyclophilinInhibitors 147
GrégoireVuagniaux,ArnaudHamel,RafaelCrabbé,HervéC.Porchet,
andJean-MauriceDumont
7.1 Introduction 147
7.2 CyclophilinOverview 148
7.3 CyclophilinInhibitorsCurrentlyinClinicalDevelopment 148
7.3.1 ChemicalStructure 149
7.3.2 CypAPPIaseInhibitionandLackofImmunosuppressive
Activity 149
7.4 CyclophilinandHIV 149
7.4.1 CyclophilinInhibitorsagainstHIV-1 151
7.4.1.1 InVitroAnti-HIV-1Activity 151
7.4.1.2 ResistanceProfile 152
7.4.1.3 InVivoActivity 152
7.4.1.4 PutativeMechanismofActionofCyclophilinInhibitors
againstHIV-1 152
7.4.1.5 ClinicalActivityofDebio025againstHIV-1 153
7.4.2 NoActivityagainstSimianImmunodeficiencyVirus 154
7.4.3 ActivityagainstHIV-2 154
7.5 CyclophilinandHepatitisC 155
7.5.1 PutativeRoleofCyclophilininHCVReplication 155
7.5.2 ActivityofCyclophilinInhibitorsinHCV 157
7.5.3 ResistanceProfile 158
7.6 ClinicalResultsinHCV 159
7.6.1 Debio025 159
7.6.1.1 Randomized,Double-Blind,Placebo-ControlledStudy
inHIV-1/HCVCoinfectedorHIV-1MonoinfectedPatients 159
7.6.1.2 Randomized,Double-Blind,Placebo-Controlled,Escalating
DoseRangingStudyofDebio025inCombinationwithPegasys
inTreatment-NaïvePatientswithChronicHepatitis 159
7.6.2 StudyofDebio025inCombinationwithPEG-IFNa2andRibavirin
inChronicHCVGenotype1NonrespondingPatients 162
7.6.3 AdverseEvents 167
7.6.4 NIM811andSCY635 167
7.7 ActivityagainstOtherViruses 167
7.8 NewNoncyclosporineCyclophilinInhibitors 168
7.8.1 PeptidesandPeptidomimetics 168
7.8.2 CsABis-UreaDerivatives 169
7.8.3 Dimedone-LikeMolecules 169
Contents IX
7.8.4 QuinoxalineDerivatives 169
7.8.5 DiarylureaDerivatives 170
7.8.6 OtherAcylureaDerivatives 171
7.9 Conclusion 173
References 173
8 AlkoxyalkylEsterProdrugsofAntiviralNucleoside
PhosphatesandPhosphonates 181
JamesR.BeadleandKarlY.Hostetler
8.1 Introduction 181
8.2 EnhancingtheOralActivityofAntiviralCompounds:Overview
oftheDevelopmentofAlkoxyalkylEsterificationApproach 182
8.3 AlkylglycerolandAlkoxyalkylProdrugsofPhosphonoformate:
EnhancedAntiviralActivityandSynergismwithAZT 185
8.4 AlkoxyalkylEstersofNucleoside50-Monophosphates 185
8.5 OralProdrugsofAcyclicNucleoside
Phosphonates 189
8.5.1 Cidofovir 189
8.5.1.1 ActivityagainstPoxvirusesInVitro 189
8.5.1.2 ActivityagainstOtherDouble-StrandedDNAVirusesInVitro 190
8.5.1.3 EfficacyofAlkoxyalkylEstersofANPsinAnimalModels
ofDisease 191
8.5.2 AlkoxyalkylEstersof(S)-HPMPA 191
8.5.3 AlkoxyalkylEstersofTenofovir(HDP-(R)-PMPA) 196
8.5.4 HexadecyloxypropylAdefovirandProdrugsofOtherANPs
andAntivirals 197
8.6 IntraocularDeliveryofAntiviralProdrugsforTreatment
orPreventionofCytomegalovirusRetinitis 198
8.6.1 1-O-Octadecyl-sn-glycero-3-phosphonoformate(ODG-PFA) 198
8.6.2 HexadecyloxypropylGanciclovir50-Monophosphate
(HDP-P-GCV) 199
8.6.3 HexadecyloxypropylEstersofCyclicCidofovirand
Cyclic(S)-HPMPA 200
8.7 Conclusion 201
References 201
9 Maribavir:ANovelBenzimidazoleRibonucleosideforthePrevention
andTreatmentofCytomegalovirusDiseases 209
KarenK.Biron
9.1 CytomegalovirusDiseases:UnmetChallenges 209
9.2 Maribavir:AntiviralActivity 210
9.3 Maribavir:MechanismsofActionandResistance 212
9.4 PreclinicalStudies 214
9.5 ClinicalDevelopmentofMaribavir:EarlyPhaseI 215
9.6 ClinicalDevelopmentinaTransplantPopulation 218