MedKoo Biosciences/Tofacitinib/200811/2g

RelatedCAS#:540737-29-9(citrate) 477600-75-2(freebase)  

Synonym:TofacitinibfreebaseCP690550;CP-690550;CP690550;Tofacitinib;tasocitinib.TradenameXeljanz

IUPAC/ChemicalName:3-((3R,4R)-4-Methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

InChiKey:UJLAWZDWDVHWOW-YPMHNXCESA-N

InChiCode:InChI=1S/C16H20N6O/c1-11-5-8-22(14(23)3-6-17)9-13(11)21(2)16-12-4-7-18-15(12)19-10-20-16/h4,7,10-11,13H,3,5,8-9H2,1-2H3,(H,18,19,20)/t11-,13+/m1/s1

SMILESCode:N#CCC(N1C[C@H](N(C)C2=C3C(NC=C3)=NC=N2)[C@H](C)CC1)=O

TechnicalData

AdditionalInformation

Itisaninhibitoroftheenzymejanuskinase3(JAK3),whichmeansthatitinterfereswiththeJAK-STATsignalingpathway,whichtransmitsextracellularinformationintothecellnucleus,influencingDNAtranscription.RecentlyithasbeenshowninamurinemodelofestablishedarthritisthattofacitinibrapidlyimproveddiseasebyinhibitingtheproductionofinflammatorymediatorsandsuppressingSTAT1-dependentgenesinjointtissue.ThisefficacyinthisdiseasemodelcorrelatedwiththeinhibitionofbothJAK1and3signalingpathways,suggestingthattofacitinibmayexerttherapeuticbenefitviapathwaysthatarenotexclusivetoinhibitionofJAK3.
 
 

References

1:CurtisJR,ZhangR,KrishnaswamiS,AnisfeldA,ChenY,StrengholtS,ChenC,GeierJ.Useofariskcharacterisationapproachtocontextualisethesafetyprofileofnewrheumatoidarthritistreatments:acasestudyusingtofacitinib.ClinRheumatol.2017Mar;36(3):683-688.doi:10.1007/s10067-016-3359-x.PubMedPMID:27470086;PubMedCentralPMCID:PMC5323490.

2:PappKA,KruegerJG,FeldmanSR,LangleyRG,ThaciD,ToriiH,TyringS,WolkR,GardnerA,MebusC,TanH,LuoY,GuptaP,MallbrisL,TatulychS.Tofacitinib,anoralJanuskinaseinhibitor,forthetreatmentofchronicplaquepsoriasis:Long-termefficacyandsafetyresultsfrom2randomizedphase-IIIstudiesand1open-labellong-termextensionstudy.JAmAcadDermatol.2016May;74(5):841-50.doi:10.1016/j.jaad.2016.01.013.PubMedPMID:26899199.

3:KruegerJ,ClarkJD,Suárez-FariñasM,Fuentes-DuculanJ,CuetoI,WangCQ,TanH,WolkR,RottinghausST,WhitleyMZ,ValdezH,vonSchackD,O'NeilSP,ReddyPS,TatulychS;A3921147StudyInvestigators..Tofacitinibattenuatespathologicimmunepathwaysinpatientswithpsoriasis:Arandomizedphase2study.JAllergyClinImmunol.2016Apr;137(4):1079-90.doi:10.1016/j.jaci.2015.12.1318.PubMedPMID:27059729.

4:LeeYH,BaeSC,SongGG.Comparativeefficacyandsafetyoftofacitinib,withorwithoutmethotrexate,inpatientswithactiverheumatoidarthritis:aBayesiannetworkmeta-analysisofrandomizedcontrolledtrials.RheumatolInt.2015Dec;35(12):1965-74.doi:10.1007/s00296-015-3291-4.PubMedPMID:25994093.

5:FukuyamaT,TschernigT,QiY,VolmerDA,BäumerW.AggressionbehaviourinducedbyoraladministrationoftheJanus-kinaseinhibitortofacitinib,butnotoclacitinib,understressfulconditions.EurJPharmacol.2015Oct5;764:278-82.doi:10.1016/j.ejphar.2015.06.060.PubMedPMID:26164790.

6:LeeMY,ParkSK,ParkSY,ByunJH,LeeSM,KoSK,LeeEK.Cost-effectivenessofTofacitinibintheTreatmentofModeratetoSevereRheumatoidArthritisinSouthKorea.ClinTher.2015Aug;37(8):1662-76.e2.doi:10.1016/j.clinthera.2015.07.001.PubMedPMID:26243076.

7:TanakaY,TakeuchiT,YamanakaH,NakamuraH,ToyoizumiS,ZwillichS.EfficacyandsafetyoftofacitinibasmonotherapyinJapanesepatientswithactiverheumatoidarthritis:a12-week,randomized,phase2study.ModRheumatol.2015Jul;25(4):514-21.doi:10.3109/14397595.2014.995875.PubMedPMID:25496464;PubMedCentralPMCID:PMC4819568.

8:KoizumiH,AritoM,EndoW,KurokawaMS,OkamotoK,OmoteyamaK,SuematsuN,BeppuM,KatoT.Effectsoftofacitinibonnucleicacidmetabolisminhumanarticularchondrocytes.ModRheumatol.2015Jul;25(4):522-7.doi:10.3109/14397595.2014.995874.PubMedPMID:25496463.

9:WallensteinGV,KanikKS,WilkinsonB,CohenS,CutoloM,FleishmannR,GenoveseMC,GomezReinoJ,GrubenD,KremerJ,KrishnaswamiS,LeeEB,Pascual-RamosV,StrandV,ZwillichSH.EffectsoftheoralJanuskinaseinhibitortofacitinibonpatient-reportedoutcomesinpatientswithactiverheumatoidarthritis:resultsoftwoPhase2randomisedcontrolledtrials.ClinExpRheumatol.2016May-Jun;34(3):430-42.PubMedPMID:27156561.

10:CurtisJR,LeeEB,KaplanIV,KwokK,GeierJ,BendaB,SomaK,WangL,RieseR.Tofacitinib,anoralJanuskinaseinhibitor:analysisofmalignanciesacrosstherheumatoidarthritisclinicaldevelopmentprogramme.AnnRheumDis.2016May;75(5):831-41.doi:10.1136/annrheumdis-2014-205847.PubMedPMID:25902789;PubMedCentralPMCID:PMC4853586.

11:WinthropKL,SilverfieldJ,RacewiczA,NealJ,LeeEB,HrycajP,Gomez-ReinoJ,SomaK,MebusC,WilkinsonB,HodgeJ,FanH,WangT,BinghamCO3rd.Theeffectoftofacitinibonpneumococcalandinfluenzavaccineresponsesinrheumatoidarthritis.AnnRheumDis.2016Apr;75(4):687-95.doi:10.1136/annrheumdis-2014-207191.PubMedPMID:25795907;PubMedCentralPMCID:PMC4819610.

12:RizziM,LorenzettiR,FischerK,StaniekJ,JanowskaI,TroiloA,StrohmeierV,ErlacherM,KunzeM,BannertB,KyburzD,VollRE,VenhoffN,ThielJ.ImpactoftofacitinibtreatmentonhumanB-cellsinvitroandinvivo.JAutoimmun.2017Feb;77:55-66.doi:10.1016/j.jaut.2016.10.005.PubMedPMID:27793425.

13:FleischmannR,MeasePJ,SchwartzmanS,HwangLJ,SomaK,ConnellCA,TakiyaL,BananisE.Efficacyoftofacitinibinpatientswithrheumatoidarthritisstratifiedbybackgroundmethotrexatedosegroup.ClinRheumatol.2017Jan;36(1):15-24.doi:10.1007/s10067-016-3436-1.PubMedPMID:27734232;PubMedCentralPMCID:PMC5216063.

14:YamanakaH,TanakaY,TakeuchiT,SugiyamaN,YuasaH,ToyoizumiS,MorishimaY,HiroseT,ZwillichS.Tofacitinib,anoralJanuskinaseinhibitor,asmonotherapyorwithbackgroundmethotrexate,inJapanesepatientswithrheumatoidarthritis:anopen-label,long-termextensionstudy.ArthritisResTher.2016Jan28;18:34.doi:10.1186/s13075-016-0932-2.PubMedPMID:26818974;PubMedCentralPMCID:PMC4730592.

15:VieiraMC,ZwillichSH,JansenJP,SmiechowskiB,SpurdenD,WallensteinGV.TofacitinibVersusBiologicTreatmentsinPatientsWithActiveRheumatoidArthritisWhoHaveHadanInadequateResponsetoTumorNecrosisFactorInhibitors:ResultsFromaNetworkMeta-analysis.ClinTher.2016Dec;38(12):2628-2641.e5.doi:10.1016/j.clinthera.2016.11.004.PubMedPMID:27889300.

16:Charles-SchoemanC,WickerP,Gonzalez-GayMA,BoyM,ZuckermanA,SomaK,GeierJ,KwokK,RieseR.Cardiovascularsafetyfindingsinpatientswithrheumatoidarthritistreatedwithtofacitinib,anoralJanuskinaseinhibitor.SeminArthritisRheum.2016Dec;46(3):261-271.doi:10.1016/j.semarthrit.2016.05.014.PubMedPMID:27443588.

17:StrandV,AhadiehS,FrenchJ,GeierJ,KrishnaswamiS,MenonS,ChecchioT,TensfeldtTG,HoffmanE,RieseR,BoyM,Gómez-ReinoJJ.Systematicreviewandmeta-analysisofseriousinfectionswithtofacitinibandbiologicdisease-modifyingantirheumaticdrugtreatmentinrheumatoidarthritisclinicaltrials.ArthritisResTher.2015Dec15;17:362.doi:10.1186/s13075-015-0880-2.Review.PubMedPMID:26669566;PubMedCentralPMCID:PMC4704538.

18:StrandV,KremerJ,WallensteinG,KanikKS,ConnellC,GrubenD,ZwillichSH,FleischmannR.Effectsoftofacitinibmonotherapyonpatient-reportedoutcomesinarandomizedphase3studyofpatientswithactiverheumatoidarthritisandinadequateresponsestoDMARDs.ArthritisResTher.2015Nov4;17:307.doi:10.1186/s13075-015-0825-9.PubMedPMID:26530039;PubMedCentralPMCID:PMC4632359.

19:FeldmanSR,ThaçiD,GooderhamM,AugustinM,delaCruzC,MallbrisL,BuonannoM,TatulychS,KaurM,LanS,ValdezH,MamoloC.Tofacitinibimprovespruritusandhealth-relatedqualityoflifeupto52weeks:Resultsfrom2randomizedphaseIIItrialsinpatientswithmoderatetosevereplaquepsoriasis.JAmAcadDermatol.2016Dec;75(6):1162-1170.e3.doi:10.1016/j.jaad.2016.07.040.PubMedPMID:27692733.

20:WuJJ,StroberBE,HansenPR,AhlehoffO,EgebergA,QureshiAA,RobertsonD,ValdezH,TanH,WolkR.EffectsoftofacitiniboncardiovascularriskfactorsandcardiovascularoutcomesbasedonphaseIIIandlong-termextensiondatainpatientswithplaquepsoriasis.JAmAcadDermatol.2016Nov;75(5):897-905.doi:10.1016/j.jaad.2016.06.012.PubMedPMID:27498960.