title: Amphipathic 3-phenyl-7-propylbenzisoxazoles; human pPaR gamma, delta and alpha agonists.
abstract: A series of amphipathic 3-phenylbenzisoxazoles were found to be potent agonists of human PPARalpha, gamma and delta. The optimization of acid proximal structure for in vitro and in vivo potency is described. Results of po dosed efficacy studies in the db/db mouse model of type 2 diabetes showed efficacy equal or superior to Rosiglitazone in correcting hyperglycemia and hypertriglyceridemia. Good functional receptor selectivity for PPARalpha and gamma over PPARdelta can be obtained.
authors.affiliation: Departments of Basic Chemistry, Merck Research Laboratories, Merck & Co. Inc., PO Box 2000, Rahway, NJ 07065, USA. alan_adams@merck.com
authors.forename: Alan D
authors.initials: AD
authors.lastname: Adams
authors.forename: Winston
authors.initials: W
authors.lastname: Yuen
authors.forename: Zao
authors.initials: Z
authors.lastname: Hu
authors.forename: Conrad
authors.initials: C
authors.lastname: Santini
authors.forename: A Brian
authors.initials: AB
authors.lastname: Jones
authors.forename: Karen L
authors.initials: KL
authors.lastname: MacNaul
authors.forename: Joel P
authors.initials: JP
authors.lastname: Berger
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Doebber
authors.forename: David E
authors.initials: DE
authors.lastname: Moller
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D019556:COS Cells; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004195:Disease Models, Animal; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D008817:Mice, Mutant Strains; D009687:Nuclear Proteins / Q000819:agonists / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D000077154:Rosiglitazone; D013844:Thiazoles / Q000493:pharmacokinetics / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists* / Q000378:metabolism
chemical_list: D007555:Isoxazoles; D009687:Nuclear Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone