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

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Furukawa A, Arita T, Satoh S, Wakabayashi K, Hayashi S, Matsui Y, Araki K, Kuroha M, Ohsumi J

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

Bioorg Med Chem Lett. 2010 Apr 1;20(7):2095-8. doi: 10.1016/j.bmcl.2010.02.073. Epub 2010 Feb 20.

PubMed ID

20219371 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Pioglitazone	Peroxisome proliferator-activated receptor gamma	EC 50 (nM)	88	N/A	N/A	Details
Rosiglitazone	Peroxisome proliferator-activated receptor gamma	EC 50 (nM)	11	N/A	N/A	Details