Discovery of a Peroxisome Proliferator Activated Receptor γ (PPARγ) Modulator with Balanced PPARα Activity for the Treatment of Type 2 Diabetes and Dyslipidemia

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• 作者：Weiguo Liu ; Kun Liu ; Harold B. Wood ; Margaret E. McCann ; Thomas W. Doebber ; Ching H. Chang ; Taro E. Akiyama ; Monica Einstein ; Joel P. Berger ; Peter T. Meinke
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：July 23, 2009
• 年：2009
• 卷：52
• 期：14
• 页码：4443-4453
• 全文大小：835K
• 年卷期：v.52,no.14(July 23, 2009)
• ISSN：1520-4804

文摘

A series of 3-acylindole-1-benzylcarboxylic acids were designed and synthesized while searching for a PPARγ modulator with additional moderate intrinsic PPARα agonistic activity. 2-[3-[[3-(4-Chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl]phenoxy]-(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 PPARγ full agonists. The moderate PPARα activity of 12d not only contributed to the agent’s ability to manage lipid profiles but also appears to have potentiated its PPARγ efficacy in lowering glucose levels in preclinical diabetic animal models.