Design, synthesis, and biological evaluation of novel constrained meta-substituted phenyl propanoic acids as peroxisome proliferator-activated receptor α and γ dual agonists

In an effort to develop dual PPARα/γ activators with improved therapeutic efficacy, a series of diaryl α-ethoxy propanoic acid compounds comprising two aryl groups linked by rigid oxime ether or isoxazoline ring were designed and synthesized and their biological activities were examined. Most of the compounds possessing an oxime ether linker were more potent PPARγ activators than the lead PPARα/γ dual agonist, tesaglitazar in vitro. Compound 18, one of the derivatives with an oxime ether linker, was found to selectively transactivate PPARγ (EC₅₀ = 0.028 μM) over PPARα (EC₅₀ = 7.22 μM) in vitro and lower blood glucose in db/db mice more than muraglitazar after oral treatment for 11 days.