(2R)-2-Ethylchromane-2-carboxylic Acids: Discovery of Novel PPARα/γ Dual Agonists as Antihyperglycemic and Hypolipidemic Agents
Journal of Medicinal Chemistry2004Vol. 47(12), pp. 3255–3263
Citations Over TimeTop 10% of 2004 papers
Hiroo Koyama, Daniel J. Miller, Julia K. Boueres, Ranjit C. Desai, A. Brian Jones, Joel P. Berger, Karen L. MacNaul, Linda Kelly, Thomas W. Doebber, Margaret Wu, Gaochao Zhou, Pei-Ran Wang, Marc C. Ippolito, Yu‐Sheng Chao, Arun K. Agrawal, Ronald B. Franklin, James V. Heck, Samuel D. Wright, David E. Moller, Soumya P. Sahoo
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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