| Literature DB >> 22070604 |
Weiguo Liu1, 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.
Abstract
A series of benzimidazolone carboxylic acids and oxazolidinediones were designed and synthesized in search of selective PPARγ modulators (SPPARγMs) 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 PPARγ full agonist drugs. Structure-activity relationships of these potent and highly selective SPPARγMs were studied with a focus on their unique profiles as partial agonists or modulators. A variety of methods, such as X-ray crystallographic analysis, PPARγ transactivation coactivator profiling, gene expression profiling, and mutagenesis studies, were employed to reveal the differential interactions of these new analogues with PPARγ 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 PPARγ full agonists, were diminished with 51 in comparison to rosiglitazone based on studies in two independent animal models.Entities:
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Year: 2011 PMID： 22070604 DOI： 10.1021/jm201061j
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446