Development of a new class of benzoylpyrrole-based PPARα/γ activators

• Published in: Bioorganic & medicinal chemistry letters 2011-01, Vol.21 (1), p.220-224
• Main Authors: Ushiroda, Kantaro, Maruta, Katsunori, Kitoh, Makoto, Iwai, Kiyotaka, Nagamine, Jun, Tsuchida, Atsushi, Taiji, Mutsuo, Nagata, Ryu
• Format: Article
• Language: English
• Subjects: Acetates - chemistry; Acetates - pharmacokinetics; Acetates - therapeutic use; Animals; Biological and medical sciences; blood; carboxylic acids; Carboxylic Acids - chemistry; Carboxylic Acids - pharmacokinetics; Carboxylic Acids - therapeutic use; General and cellular metabolism. Vitamins; Hyperglycemia - drug therapy; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - pharmacokinetics; Hypoglycemic Agents - therapeutic use; Male; Medical sciences; Mice; Mice, Obese; Obesity - drug therapy; Pharmacology. Drug treatments; PPAR alpha - agonists; PPAR alpha - metabolism; PPAR gamma - agonists; PPAR gamma - metabolism; PPARα/γ modulator; Pyrroles - chemistry; Pyrroles - pharmacokinetics; Pyrroles - therapeutic use; Rats; Structure-Activity Relationship; transforming growth factor beta; Type 2 diabetes; weight gain
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.11.032

TGF-β signaling pathway inhibitor and potential anti-nephropathic agent SMP-534 was successfully converted to a new class of benzoylpyrrole-based PPARα/γ activators as an anti-diabetic agent. Compound 10sNa showed a favorable blood glucose-lowering effect without body weight gain. Starting with a subtle blood glucose-lowering effect of a TGF-β inhibitor, we designed and synthesized a series of benzoylpyrrole-based carboxylic acids as PPARs activators. Among these compounds, 10sNa exhibited favorable blood glucose-lowering effect without body weight gain. We assume that the beneficial effect of 10sNa is attributed to not only its compound PPARα agonistic activity but also its PPARγ partial agonistic activity.