Design and Synthesis of α-Aryloxy-α-methylhydrocinnamic Acids:  A Novel Class of Dual Peroxisome Proliferator-Activated Receptor α/γ Agonists

The design and synthesis of the dual peroxisome proliferator activated receptor (PPAR) alpha/gamma agonist (S)-2-methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)ethoxy]pheny}-2-phenoxypropionic acid (2) for the treatment of type 2 diabetes and associated dyslipidemia are described. 2 possesses a potent dual hPPAR alpha/gamma agonist profile (IC50 = 28 and 10 nM; EC50 = 9 and 4 nM, respectively, for hPPARalpha and hPPARgamma). In preclinical models, 2 substantially improves insulin sensitivity and potently reverses diabetic hyperglycemia while significantly improving overall lipid homeostasis.