Antiviral Drug Strategies (Methods and Principles in Medicinal Chemistry, Volume 50) PDF
Preview Antiviral Drug Strategies (Methods and Principles in Medicinal Chemistry, Volume 50)
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 SeriesEditors AllbookspublishedbyWiley-VCHarecarefully produced.Nevertheless,authors,editors,and Prof.Dr.RaimundMannhold publisherdonotwarranttheinformationcontained? MolecularDrugResearchGroup inthesebooks,includingthisbook,tobefreeof Heinrich-Heine-Universität errors.Readersareadvisedtokeepinmindthat Universitätsstrasse1 statements,data,illustrations,proceduraldetailsor 40225Düsseldorf otheritemsmayinadvertentlybeinaccurate. Germany [email protected] LibraryofCongressCardNo.: appliedfor Prof.Dr.HugoKubinyi BritishLibraryCataloguing-in-PublicationData Donnersbergstrasse9 Acataloguerecordforthisbookisavailablefromthe 67256WeisenheimamSand BritishLibrary. Germany [email protected] Bibliographicinformationpublishedby theDeutscheNationalbibliothek Prof.Dr.GerdFolkers TheDeutscheNationalbibliothekliststhis CollegiumHelveticum publicationintheDeutscheNationalbibliografie; STW/ETHZurich detailedbibliographicdataareavailableonthe 8092Zurich Internetathttp://dnb.d-nb.de. Switzerland [email protected] #2011Wiley-VCHVerlag&Co.KGaA, Boschstr.12,69469Weinheim,Germany VolumeEditor Allrightsreserved(includingthoseoftranslationinto Prof.Dr.ErikDeClercq otherlanguages).Nopartofthisbookmaybe RegaInst.MedicalResearch reproducedinanyform–byphotoprinting, UniversityofLeuven microfilm,oranyothermeans–nortransmittedor Minderbroedersstraat10 translatedintoamachinelanguagewithoutwritten 3000Leuven permissionfromthepublishers.Registerednames, Belgium trademarks,etc.usedinthisbook,evenwhennot specificallymarkedassuch,arenottobeconsidered CoverDescription unprotectedbylaw. Recentapproachesonhowtocombatvirusinfec- tions,i.e.HIV,HCV,HSV,HCMVandinfluenza Typesetting ThomsonDigital,Noida,India virus. PrintingandBinding betz-druckGmbH,Darmstadt HIV-Protease,PDBcode3k4v(F.M.Olajuyigbeetal., CoverDesign SchulzGrafik-Design,Fußgönheim ACSMed.Chem.Lett.2010asap,DOI: 10.1021/ ml100046d);proteinbackbonegeneratedwith PrintedintheFederalRepublicofGermany LigandScout3.0,inte:ligand Printedonacid-freepaper ISBNPrint:978-3-527-32696-9 ISBNoBook:978-3-527-63595-5 ISBNePDF:978-3-527-63597-9 ISBNePub:978-3-527-63596-2 ISBNMobi:978-3-527-63598-6 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
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