Synthesis and Identification of [1,2,4]Thiadiazole Derivatives as a New Series of Potent and Orally Active Dual Agonists of Peroxisome Proliferator-Activated Receptors α and δ

Cardiovascular disease is the most common cause of morbidity and mortality in developed nations. To effectively target dyslipidemia to reduce the risk of cardiovascular disease, it may be beneficial to activate the peroxisome proliferator-activated receptors (PPARs) PPARα and PPARδ simultaneously through a single molecule. Replacement of the methylthiazole of 5 (the PPARδ selective agonist) with [1,2,4]thiadiazole gave compound 13, which unexpectedly displayed submicromolar potency as a partial agonist at PPARα in addition to the high potency at PPARδ. Optimization of 13 led to the identification of 24 as a potent and selective PPARα/δ dual agonist. Compound 24 and its close analogs represent a new series of PPARα/δ dual agonists. The high potency, significant gene induction, excellent PK profiles, and good in vivo efficacies in three animal models may render compound 24 as a valuable pharmacological tool in elucidating the complex roles of PPARα/δ dual agonists and as a potential treatment of the metabol...