Bioorganic & Medicinal Chemistry Letters 2010-04-01

Discovery of a novel selective PPARgamma modulator from (-)-Cercosporamide derivatives.

Akihiro Furukawa, Tsuyoshi Arita, Susumu Satoh, Kenji Wakabayashi, Shinko Hayashi, Yumi Matsui, Kazushi Araki, Masanori Kuroha, Jun Ohsumi

Index: Bioorg. Med. Chem. Lett. 20(7) , 2095-8, (2010)

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Abstract

In an investigation of (-)-Cercosporamide derivatives with a plasma glucose-lowering effect, we found that N-benzylcarboxamide derivative 4 was a partial agonist of PPARgamma. A SAR study of the substituents on carboxamide nitrogen afforded the N-(1-naphthyl)methylcarboxamide derivative 23 as the most potent selective PPARgamma modulator. An X-ray crystallography study revealed that compound 23 bounded to the PPARgamma ligand binding domain in a unique way without any interaction with helix12. Compound 23 displayed a potent plasma glucose-lowering effect in db/db mice without the undesirable increase in body fluid and heart weight that is typically observed when PPARgamma full agonists are administrated.2010 Elsevier Ltd. All rights reserved.