Amphipathic 3-phenyl-7-propylbenzisoxazoles; human pPaR gamma, delta and alpha agonists.
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.
Adams
Alan D
AD
Departments of Basic Chemistry, Merck Research Laboratories, Merck & Co. Inc., PO Box 2000, Rahway, NJ 07065, USA. alan_adams@merck.com
Yuen
Winston
W
Hu
Zao
Z
Santini
Conrad
C
Jones
A Brian
AB
MacNaul
Karen L
KL
Berger
Joel P
JP
Doebber
Thomas W
TW
Moller
David E
DE
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
D007555:Isoxazoles; D009687:Nuclear Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone