Benzimidazolones: A New Class of Selective Peroxisome Proliferator-Activated Receptor 纬 (PPAR纬) Modulators

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• 作者：Weiguo Liu ; Fiona Lau ; Kun Liu ; Harold B. Wood ; Gaochao Zhou ; Yuli Chen ; Ying Li ; Taro E. Akiyama ; Gino Castriota ; Monica Einstein ; Chualin Wang ; Margaret E. McCann ; Thomas W. Doebber ; Margaret Wu ; Ching H. Chang ; Lesley McNamara ; Brian McKeever ; Ralph T. Mosley ; Joel P. Berger ; Peter T. Meinke
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：December 22, 2011
• 年：2011
• 卷：54
• 期：24
• 页码：8541-8554
• 全文大小：594K
• 年卷期：v.54,no.24(December 22, 2011)
• ISSN：1520-4804

文摘

A series of benzimidazolone carboxylic acids and oxazolidinediones were designed and synthesized in search of selective PPAR纬 modulators (SPPAR纬Ms) as potential therapeutic agents for the treatment of type II diabetes mellitus (T2DM) with improved safety profiles relative to rosiglitazone and pioglitazone, the currently marketed PPAR纬 full agonist drugs. Structure鈥揳ctivity relationships of these potent and highly selective SPPAR纬Ms were studied with a focus on their unique profiles as partial agonists or modulators. A variety of methods, such as X-ray crystallographic analysis, PPAR纬 transactivation coactivator profiling, gene expression profiling, and mutagenesis studies, were employed to reveal the differential interactions of these new analogues with PPAR纬 receptor in comparison to full agonists. In rodent models of T2DM, benzimidazolone analogues such as (5R)-5-(3-{[3-(5-methoxybenzisoxazol-3-yl)benzimidazol-1-yl]methyl}phenyl)-5-methyloxazolidinedione (51) demonstrated efficacy equivalent to that of rosiglitazone. Side effects, such as fluid retention and heart weight gain associated with PPAR纬 full agonists, were diminished with 51 in comparison to rosiglitazone based on studies in two independent animal models.