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Methods for the Discovery of Novel Compounds Modulating a Gamma-Aminobutyric Acid Receptor Type A Neurotransmission
Published on: August 16, 2018
Amphipathic 3-phenyl-7-propylbenzisoxazoles; human pPaR gamma, delta and alpha agonists
Alan D Adams1, Winston Yuen, Zao Hu
1Departments of Basic Chemistry, Merck Research Laboratories, Merck & Co. Inc., PO Box 2000, Rahway, NJ 07065, USA. alan_adams@merck.com
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.
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