一个口服的选择性肽环氧酮的蛋白酶抑制剂的设计与合成中英文对照

Abbreviations:CT-L,chymotrypsin-like;T-L,trypsin-like;C-L,caspase-3028J.Med.Chem.2009,52,3028–3038DesignandSynthesisofanOrallyBioavailableandSelectivePeptideEpoxyketoneProteasomeInhibitor(PR-047)ProteasomeinhibitionhasbeenvalidatedasatherapeuticmodalityinthetreatmentofmultiplemyelomaandNon-Hodgkin’slymphoma.Carfilzomib,anepoxyketonecurrentlyundergoingclinicaltrialsinmalignantdiseases,isahighlyselectiveinhibitorofthechymotrypsin-like(CT-L)activityoftheproteasome.Achemistryeffortwasinitiatedtodiscoverorallybioavailableanaloguesofcarfilzomib,whichwouldhavepotentialforimproveddosingflexibilityandpatientconvenienceoverintravenouslyadministeredagents.Theleadcompound,2-Me-5-thiazole-Ser(OMe)-Ser(OMe)-Phe-ketoepoxide(58)(PR-047),selectivelyinhibitedCT-Lactivityofboththeconstitutiveproteasome(5)andimmunoproteasome(LMP7)anddemonstratedanabsolutebioavailabilityofupto39%inrodentsanddogs.Itwaswelltoleratedwithrepeatedoraladministrationatdosesresultingin80%proteasomeinhibitioninmosttissuesandelicitedanantitumorresponseequivalenttointravenouslyadministeredcarfilzomibinmultiplehumantumorxenograftandmousesyngeneicmodels.Thefavorablepharmacologicprofilesupportsitsfurtherdevelopmentforthetreatmentofmalignantdiseases.IntroductionTheproteasomeisamulticatalyticproteasecomplexthatisresponsiblefortheubiquitin-dependentturnoverofcellularproteins.1-3Proteasomesubstratesincludemisfoldedormis-assembledproteinsaswellasshort-livedcomponentsofsignalingcascadesthatregulatecellproliferationandsurvivalpathways.Inhibitionoftheproteasomeleadstoanaccumulationofsubstrateproteinsandresultsincelldeath.4Theproteasomeconsistsofa20Sproteolyticcoreandtwo19Sregulatorycapsthatassemblewiththecoreateitherendtoforma26Scomplex.5,6Twodistinctformsofthe26Sproteasome,theconstitutiveproteasomeandtheimmunoproteasome,havebeenidentified.Themajorityofcelltypesexpresstheconstitutiveformoftheproteasome,whilecellsoftheimmunesystemexpresstheimmunoproteasome.Nonimmunecellscanalsoexpressimmunoproteasomesfollowingexposuretoinflamma-torycytokinessuchasinterferonγ(IFN-γ).The20Scoreoftheconstitutiveproteasomehasthreedistinctcatalyticactivities:chymotrypsin-like(CT-La),trypsin-like(T-L),andcaspase-like(C-L),whichareencodedbythe5,2,and1subunits,respectively.Ofthese,theCT-Lactivityisthoughttobetherate-limitingstepofproteolysisinvitroandinvivo,whileinhibitionofmultiplesitesmightberequiredtofullysuppressproteasome-mediatedproteinturnover.7,8Theimmunoprotea-someretainsthestructuralsubunitsoftheconstitutiveprotea-somebutincorporatesthecatalyticsubunitsLMP7,MECL1,andLMP2inplaceof5,2,and1,respectively.9-12Eachproteasomeactivesiteutilizesthenucleophilicγ-hydroxylgroupofanamino-terminalthreonine(Thr)residuetoinitiateamide*Towhomcorrespondenceshouldbeaddressed.Phone:[phone].Fax:[phone].E-mail:[e-mail];MDR,multidrugresistancetransporters;SGF,simulatedgastricfluids;SIF,simulatedintestinalfluids;iv,intravenousadministration;po,oraladministration;PK,pharmacokinetics;PD,pharmacodynamics;DLT,doselimitingtoxicities;MTD,maximumtolerateddose.10.1021/jm801329vCCC:$40.75bondhydrolysisandactivationofnucleophilicwaterbytheR-aminogrouptohydrolyzetheresultingester.Clinicalvalidationoftheproteasomeasatherapeutictargetinoncologyhasbeenprovidedbybortezomib1(Figure1),adipeptideboronicacid,4,13whichisapprovedforthetreatmentofpatientswithmultiplemyeloma14-17andmantlecelllymphoma.18,19Althoughtheclinicalsuccessofbortezomibisencouraging,asignificantfractionofpatientsrelapseorarerefractorytotreatment.14-19Additionally,dose-limitingtoxici-ties(DLT),includingapainfulperipheralneuropathyandthrombocytopenia,havebeenreported.16,20,21Itisunclearwhetherthesetoxicitiescanbeattributedtooff-targeteffectsbecausebortezomibinhibitsotherenzymessuchasserineproteases,albeitwithlowerpotencies.13,22,23Recently,wereportedthediscoveryofcarfilzomib2(alsocalledPR-171),22,23astructuralanalogueofthemicrobialnaturalproductepoxo-micin3thatwasinitiallyidentifiedforitsantitumoractivityandsubsequentlyshowntobeapotentinhibitoroftheproteasome.24-28CarfilzomibselectivelyinhibitstheCT-Lactivityofthe20Sproteasomeanddisplaysequivalentpotencyagainst5andLMP7withminimalcrossreactivitytootherproteaseclasses.PreclinicalstudiesandphaseIclinicalstudiesdemonstratedthatconsecutivedaydosingscheduleswithcarfilzomibarebothwelltoleratedandpromoteantitumoractivityinhematologicmalignancies,includingpatientsprevi-ouslytreatedwithbortezomib.22,23,29-33CarfilzomibiscurrentlybeingevaluatedinphaseIandphaseIIclinicaltrialsinmultiplemyeloma,non-Hodgkin’slymphoma,andsolidtumors.Clinicalresponsestoproteasomeinhibitortherapyrequirefrequentdosing(e.g.,twiceperweek)andprolongedtreatment.Bothbortezomibandcarfilzomibareadministeredintravenously(iv)onbiweeklyormorefrequentdosingscheduleswithtreatmentthatcanextendforover6months.23Therefore,thedevelopmentoforallybioavailableproteasomeinhibitorsthatwouldallowfordosingflexibilityandimprovepatientconven-ienceiswarranted.Wedescribeheretheresultsofsystematic2009AmericanChemicalSocietyPublishedonWeb04/06/2009PeptideE