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.