(2R)-2-Ethylchromane-2-carboxylic acids: Discovery of novel PPARα/γ dual agonists as antihyperglycemic and hypolipidemic agents

A series of chromane-2-carboxylic acid derivatives was synthesized and evaluated for PPAR agonist activities. A structure−activity relationship was developed toward PPARα/γ 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 PPARα/γ 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.