Discovery of cyclic amine-substituted benzoic acids as PPARα agonists

Abstract A series of novel cyclic amine-substituted benzoic acid derivatives were synthesized and evaluated for their PPARα agonist activity. Strucure-activity relationship studies led to the identification of ( S )-3-[3-[2-(4-chlorophenyl)-4-methylthyazole-5-carboxamido]piperidin-1-yl]benzoic acid ( S )- 4f (KRP-105) as a potent and high subtype-selective human PPARα agonist. ( S )- 4f showed excellent PK profile and oral administration of ( S )- 4f to high-fat diet dogs effectively lowered triglycerides.