(2R)-2-ethylchromane-2-carboxylic acids: discovery of novel PPARalpha/gamma dual agonists as antihyperglycemic and hypolipidemic agents |
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Authors: | Koyama Hiroo Miller Daniel J Boueres Julia K Desai Ranjit C Jones A Brian Berger Joel P MacNaul Karen L Kelly Linda J Doebber Thomas W Wu Margaret S Zhou Gaochao Wang Pei-ran Ippolito Marc C Chao Yu-Sheng Agrawal Arun K Franklin Ronald Heck James V Wright Samuel D Moller David E Sahoo Soumya P |
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Affiliation: | Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065-0900, USA. hiroo_koyama@merck.com |
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Abstract: | A series of chromane-2-carboxylic acid derivatives was synthesized and evaluated for PPAR agonist activities. A structure-activity relationship was developed toward PPARalpha/gamma dual agonism. As a result, (2R)-7-(3-[2-chloro-4-(4-fluorophenoxy)phenoxy]propoxy)-2-ethylchromane-2-carboxylic acid (48) was identified as a potent, structurally novel, selective PPARalpha/gamma dual agonist. Compound 48 exhibited substantial antihyperglycemic and hypolipidemic activities when orally administered in three different animal models: the db/db mouse type 2 diabetes model, a Syrian hamster lipid model, and a dog lipid model. |
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