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) α/γ agonist (S)-2-methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)ethoxy]-phenyl}-2-phenoxypropionic acid (2) for the treatment of type 2 diabetes and associated dyslipidemia are described. 2 possesses a potent dual hPPAR α/γ agonist profile (IC 50 = 28 and 10 nM; EC 50 = 9 and 4 nM, respectively, for hPPARa and hPPARγ). In preclinical models, 2 substantially improves insulin sensitivity and potently reverses diabetic hyperglycemia while significantly improving overall lipid homeostasis.