PPAR-激动剂的研究进展-张瑜

ChineseJournalofNewDrugs20152477712015247“”2013ZX09401004。[e-mail]。。[e-mail]。。[e-mail]。··PPAＲγ010059peroxisomeproliferator-activatedreceptorPPAＲ、。PPAＲPPAＲγ。PPAＲγＲ914A1003－3734201507－0771－07ＲesearchprogressofPPAＲγagonistsZHANGYuXINGZhi-jiaMAYu-hengYANGHuiCollegeofPharmacyInnerMongoliaMedicinalUniversityHuhhot010059ChinaAbstractPeroxisomeproliferator-activatedreceptorsPPAＲsplayacrucialroleinmetabolicregulationofglucoseslipidsandcholesterolsandnowtheyhavebeenimportanttherapeutictargetsformetabolicsyndromeMS．ThisreviewcoveredthestructuresandfunctionsofPPAＲsandtheprogressofPPAＲγagonists．KeywordsPPAＲγagonistsperoxisomeproliferator-activatedreceptorresearchprogressPeroxisomeproliferator-activatedreceptorPPAＲnuclearhormonerecptor1PeroxisomeProliferators。PPAＲ2GreenIssemann19902。1997KliewerFormanLIC、EicosapentaenoicacidEPAPPAＲ3－4。PPAＲ、MetabolicsyndromeMS5。1PPAＲPPAＲ3αβδγ6。PPAＲ34A/BCDE。A/BNPPAＲ17。C70DNADNAbindingdo-mainDBD2。PPAＲperoxi-someproliferatorresponseelementPPＲE。D。ECligandbind-ingdomainLBDAF-221SＲC21、CCAATTCBP。ChineseJournalofNewDrugs20152477722015247APPAＲAF-1=-1DBD=DNALBD=AF-2=-2．BPPAＲsDNA1PPAＲPPAＲs3。PPAＲα、、8PPAＲβ、PPAＲγ9。PPAＲγ、。PPAＲγwhiteadipocytes10。PPAＲγII、。2PPAＲγ2．1PPAＲγ1-24-thiazolideinedionesTZDs12。10。21～6ciglitazone2211。TZD。troglitazone3212E2。199713。pio-glitazone4214rosiglitazone52152。englitazone6216BB45。1TDZsBB4-。-24--24-、。1、ChineseJournalofNewDrugs2015247773201524717。1BC2C。52--5-73218。DＲF-218983518PPAＲ。C9319。Ser-432。9。9PPAＲγ。37～142。103PPAＲγ1053PPAＲαPPAＲβ20。5。DaiichiSankyo102009IIIII。BM13．1258113BM15．2054123BPPAＲγ。PPAＲγ。111221。1332-CB4522。efatutazone143540PPAＲPPAＲγ。PPAＲγ。efatutazone23DaiichiSankyoII。C5ChineseJournalofNewDrugs20152477742015247。S5S24。551516425。PPAＲγ。PPAＲγ。。17426C。26。415～172．2-24-C5A。-24-PPAＲγ。α13-。-24-18527。-24-α-PPAＲγSB213068195。A1924-α。α。SＲPPAＲγ28。19BB2021519αS29。。518～25ChineseJournalofNewDrugs201524777520152472223530。①。②2ＲII。2452-PPAＲγ———2-31。2425532PPAＲγPPAＲα。25IIdb/dbZDF。PPAＲγPPAＲα/γ26276334-PPAＲγX-4-。αＲ286PPAＲγS34。2PPAＲγX-12α。626～31Henke355-PPAＲγGW0207296。329、。Sauer-berg36303165PPAＲγ。PPAＲ。PPAＲγ327-2-37。337PPAＲγ38－39XPPAＲγLBD。347ChineseJournalofNewDrugs20152477762015247PPAＲγCOX40－41。5L-FABPaP2PPAＲγ。732～343PPAＲ20、、PPAＲ。PPAＲγ。PPAＲγ。-24-PPAＲ。、PPAＲγ、、。1MICHALIKLWAHLIW．Peroxisomeproliferator2acti2vatedreceptorsthreeisotypesforamultitudeoffunctionsJ．CurrOpinBiotechnol1999106564－570．2ISSEMANNIGＲEENS．ActivationofamemberofthesteroidhormonereceptorsuperfamilybyperoxisomeproliferatorsJ〗．Nature19903476294645－650．3KLIEWEＲSASUNDSETHSSJONESSAetal．Fattyacidsandeicosanoidsregulategeneexpressionthroughdirectinterac-tionswithperoxisomeproliferator-activatedreceptorsalphaandgammaJ．PNAS19979494318－4323．4FOＲMANBMCHENJEVANSＲM．Hypolipidemicdrugspolyunsaturatedfattyacidsandeicosanoidsareligandsforperox-isomeproliferator2activatedreceptorsalphaanddeltaJ．PNAS19979494312－4317．5BEＲGEＲJPAKIYAMATEMEINKEPT．PPAＲstherapeu-tictargetsformetabolicdiseaseJ．TrendsPharmSci2005265244－251．6SHEAＲEＲBGBILLINAN．ThenextgenerationofPPAＲdrugsDowehavethetoolstofindthemJ．BiochimBiophysActa2007177181082－1093．7SHAODＲANGWALASMBAILEYSTetal．InterdomaincommunicationregulatingligandbindingbyPPAＲ-γJ．Na-ture19983966709377－380．8AUBOEFDＲIEUSSETJFAJASLetal．TissuedistributionandquantificationoftheexpressionofmＲNAsofperoxisomepro-liferators-activatedreceptorsandliverXreceptor-alphainhu-mansnoalterationinadiposetissueofobeseandNIDDMpa-tientsJ．Diabetes19974681319－1327．9FAJASLFＲUCHAＲTJCAUWEＲXJ．PPAＲgamma3mＲNAadistinctPPAＲgammamＲNAsubtypetranscribedfromandinde-pendentpromoterJ．FEBSLett19984381－255－60．10OKUNOATAMEMOTOHTOBEKetal．Troglitazonein-creasesthenumberofsmalladipocyteswithoutthechangeofwhiteadiposetissuemassinobeseZuckerratsJ．JClinInvest199810161354－1361．11LOHＲAYBBBHUSHANVＲAOBPetal．NoveleuglycemicandhypolipidemicagentsJ．JMedChem199841101619－1630．12YOSHIOKATFUJITATKANAITetal．Studiesonhinderedphenolsandanalogues．HypolipidemicandhypoglycemicagentswithabilitytoinhibitlipidperoxidationJ．JMedChem1989322421－428．13GＲOSSBSTAELSB．PPAＲagonistsmultimodaldrugsforthetreatmentoftype-2diabetesJ．BestPractＲesClinEndocrinolMetab2007214687－710．14MOMOSEYMEGUＲOKIKEDAHetal．Studiesonantidia-beticagents．X．SynthesisandbiologicalactivitiesofpioglitazoneandrelatedcompoundsJ．ChemPharmBull19913961440－1445．15CANTELLOBCCAWTHOＲNEMACOTTAMGPetal．omega-Heterocyclylaminoalkoxybenzyl-24-thiazolidine-dionesaspotentantihyperglycemicagentsJ．JMedChem199437233977－3985．ChineseJournalofNewDrugs2015247777201524716CLAＲKDAGOLDSTEINSWVOLKMANNＲAetal．Substi-tuteddihydrobenzopyrananddihydrobenzofuranthiazolidine-24-dionesashypoglycemicagentsJ．JMedChem1991341319－325．17PICAＲDFAUWEＲXJ．PPAＲγandglucosehomeostasisJ．AnnuＲevNutr200222167－197．18SOHDATMIZUNOKMOMOSEYetal．Novelthiazolidine-dionederivativesaspotenthypoglycemicandhypolipidemica-gentsJ．JMedChem199235142617－2626．19CHITTIBOYINAAGVENKATＲAMANMSMIZUNOCSetal．Designandsynthesisofthefirstgenerationofdithiolanethia-zolidinedione-andphenylaceticacid-basedPPAＲgagonistsJ．JM