吡啶甲基上氯

5-Lipoxygenase-ActivatingProtein(FLAP)Inhibitors.Part4:Developmentof3-[3-tert-Butylsulfanyl-1-[4-(6-ethoxypyridin-3-yl)benzyl]-5-(5-methylpyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethylpropionicAcid(AM803),aPotent,Oral,OnceDailyFLAPInhibitorNicholasS.Stock,*,†GretchenBain,‡JasmineZunic,†YiweiLi,†JeannieZiff,†JeffreyRoppe,†AngelinaSantini,‡JaniceDarlington,‡PatProdanovich,‡ChristopherD.King,§ChristopherBaccei,§CatherineLee,§HaojingRong,§CharlesChapman,‡AlexBroadhead,‡DanLorrain,‡LuciaCorrea,‡JohnH.Hutchinson,†JillyF.Evans,‡andPeppiPrasit†Departmentsof†Chemistry,‡Biology,and§DrugMetabolism,AmiraPharmaceuticals,9535WaplesRoad,Suite100,SanDiego,California92121,UnitedStates*SSupportingInformationABSTRACT:Thepotent5-lipoxygenase-activatingprotein(FLAP)inhibitor3-[3-tert-butylsulfanyl-1-[4-(6-ethoxypyridin-3-yl)benzyl]-5-(5-methylpyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethylpropionicacid11ccisdescribed(AM803,nowGSK2190915).BuildinguponAM103(1)(Hutchinsonetal.J.MedChem.2009,52,5803−5815;Stocketal.Bioorg.Med.Chem.Lett.2010,20,213−217;Stocketal.Bioorg.Med.Chem.Lett.2010,20,4598−4601),SARstudiescenteringaroundthepyridinemoietyledtothediscoveryofcompoundsthatexhibitsignificantlyincreasedpotencyinahumanwholebloodassaymeasuringLTB4inhibitionwithlongerdrugpreincubationtimes(15minvs5h).Furtherstudiesidentified11ccwithapotencyof2.9nMinFLAPbinding,anIC50of76nMforinhibitionofLTB4inhumanblood(5hincubation)andexcellentpreclinicaltoxicologyandpharmacokineticsinratanddog.11ccalsodemonstratedanextendedpharmacodynamiceffectinarodentbronchoalveolarlavage(BAL)model.Thiscompoundhassuccessfullycompletedphase1clinicalstudiesinhealthyvolunteersandiscurrentlyundergoingphase2trialsinasthmaticpatients.■INTRODUCTIONTheleukotrienes(LTs)areafamilyofeicosanoidbioactivelipidsimplicatedinavarietyofpathophysiologicalstatessuchasasthma,allergicrhinitis,andatherosclerosis.Biosynthesisofleukotrienesisinitiatedthroughanimmune,allergic,orinflammatorystimulus.2Theyarederivedfromarachidonicacid(AA)throughtheconcertedactionoftheenzyme5-lipoxygenase(5-LO)with5-lipoxygenaseactivatingprotein(FLAP),initiallyconvertingAAto(5S,6E,8Z,11Z,14Z)-5-hydroperoxy-6,8,11,14-eicosatetraenoicacid(5-HpETE,Figure1).Subsequentdehydrationof5-HpETEyieldsleukotrieneA4(LTA4),anunstableepoxidethatistransformedtoeitherleukotrieneB4(LTB4)bytheenzymeLTA4hydrolaseorleukotrieneC4(LTC4)viaconjugationofglutathionebyLTC4synthase.5-HpETEcanalternativelybeconvertedto5-oxo-ETE,apotenthumanchemoattractantforeosinophils,immunecellsthatplayimportantrolesinavarietyofdiseasesincludingasthmaandcardiovasculardisease(CVD).3LTC4isfurthermetabolizedtoleukotrieneD4(LTD4)andleukotrieneE4(LTE4)throughsequentialamidebondcleavages,andcollectivelythesethreemoleculesareknownasthecysteinylleukotrienes(CysLTs)orhistoricallyastheslow-reactingsubstanceofanaphylaxis(SRS-A).ThebiologicaleffectsoftheLTsarisethroughbindingtotheirrespectiveG-protein-coupledreceptors(GPCRs).4LTB4bindstotwodistinctGPCRs,namely,BLT1andBLT2,resultinginneutrophilandeosinophilchemotaxis.5TheCysLTsactivateatleasttwowell-definedGPCRs,namely,CysLT16andCysLT2,7theactivationoftheformerleadingtocontractionofsmoothmuscle(bronchocon-striction),edema,eosinophilmigration,andmucussecretion.ThepreciseroleoftheCysLT2receptorremainsunclear,butmicedeficientinthisreceptorindicatearoleforCysLT2invascularpermeabilityandinflammation8anditsexpressioninmyocytes,fibroblasts,andvascularsmoothmusclecellsmaypointtoafunctionwithinthecardiovascularsystem.9RecentevidencealsopointstotheexistenceofotherreceptorsthatmaypreferentiallybindCysLTs,namely,GPR17,10P2Y12,11andaputativeCysLTEreceptor.12Received:June27,2011Published:November7,2011Articlepubs.acs.org/jmc©2011AmericanChemicalSociety8013dx.doi.org/10.1021/jm2008369|J.Med.Chem.2011,54,8013−8029ChemicalinterferenceintheLTpathwayisnotanovelconcept,asbotha5-LOinhibitor(zileuton,3)andCysLT1receptorantagonists(e.g.,montelukast,2)(Figure2)arecurrentlymarketedforthetreatmentofasthma.Direct5-LOinhibitionhasbeenanactiveresearchareaforseveraldecades,andonlytheironchelator(redoxinhibitor)3isusedclinically,withnononredoxinhibitorscurrentlyonthemarket.However,3isnotwidelyprescribedforasthmabecauseofahighdoseregimen(600mgq.i.d.or1200mgb.i.d.),lowbutsignificanthepatotoxicity,andsubsequentneedforliverfunctiontesting.132,aCysLT1receptorantagonist,iswidelyprescribedtoasthmaticsbecauseofitsefficacy,excellentsafetyprofile,andlowdosingrequirements(10mgq.d.).CysLT1antagonismobviouslyonlyblockstheactionofthisreceptoranddoesnotperturbthebiosynthesisorpathophysiologicalactionoftheotherLTs.SeveralclinicaltrialshaveevaluatedFLAPinhibitors(DG-031/BAYX10054,14MK-8865,15MK-591616)inhumanandshownthemtobeeffective.Forvariousreasons,noneofthesecompoundshavereachedthemarket.Develop-mentofcompounds4and5waslikelyhaltedbecauseofincompleteLTsynthesisinhibitionatclinicallytolerabledoses,andcompound6washaltedafterphase2trialsinfavoroftheLTD4receptorantagonist2.17SignificantevidencealsopointstothepotentialforLTinhibitorstohaveapositiveimpactonCVD.Gene