Discovery of a peroxisome proliferator activated receptor gamma (PPARgamma) modulator with balanced PPARalpha activity for the treatment of type 2 diabetes and dyslipidemia.

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Liu W, Liu K, Wood HB, McCann ME, Doebber TW, Chang CH, Akiyama TE, Einstein M, Berger JP, Meinke PT

Discovery of a peroxisome proliferator activated receptor gamma (PPARgamma) modulator with balanced PPARalpha activity for the treatment of type 2 diabetes and dyslipidemia.

J Med Chem. 2009 Jul 23;52(14):4443-53. doi: 10.1021/jm900367w.

PubMed ID
19530681 [ View in PubMed
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Abstract

A series of 3-acylindole-1-benzylcarboxylic acids were designed and synthesized while searching for a PPARgamma modulator with additional moderate intrinsic PPARalpha agonistic activity. 2-[3-[[3-(4-Chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl]phe noxy]-(2R)-butanoic acid (12d) was identified as such an agent which demonstrated potent efficacy in lowering both glucose and lipids in multiple animal models with significantly attenuated side effects such as fluid retention and heart weight gain associated with PPARgamma full agonists. The moderate PPARalpha activity of 12d not only contributed to the agent's ability to manage lipid profiles but also appears to have potentiated its PPARgamma efficacy in lowering glucose levels in preclinical diabetic animal models.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
FenofibratePeroxisome proliferator-activated receptor alphaIC 50 (nM)1000N/AN/ADetails
FenofibratePeroxisome proliferator-activated receptor alphaEC 50 (nM)2000N/AN/ADetails
RosiglitazonePeroxisome proliferator-activated receptor alphaIC 50 (nM)>50000N/AN/ADetails
RosiglitazonePeroxisome proliferator-activated receptor alphaEC 50 (nM)>3000N/AN/ADetails
RosiglitazonePeroxisome proliferator-activated receptor gammaEC 50 (nM)20N/AN/ADetails
RosiglitazonePeroxisome proliferator-activated receptor gammaIC 50 (nM)200N/AN/ADetails