Design and synthesis of novel and potent amide linked PPARγ/δ dual agonists

Abstract A series of potent amide linked PPARγ/δ dual agonists ( 1a ) has been discovered through rational design. In the ZDF rat model of type 2 diabetes, compound ( R )-3-[4-(3-{1-[(5-chloro-1,3-dimethyl-1 H -indole-2-carbonyl)-amino]-ethyl}-5-fluoro-phenoxy)-2-ethyl-phenyl]-propionic acid ( 42 ) from this series has demonstrated glucose lowering efficacy comparable to the marketed PPARγ agonist rosiglitazone with less weight gain.