Benzimidazolones: a new class of selective peroxisome proliferator-activated receptor gamma (PPARgamma) modulators.

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Liu W, Lau F, Liu K, Wood HB, Zhou G, Chen Y, Li Y, Akiyama TE, Castriota G, Einstein M, Wang C, McCann ME, Doebber TW, Wu M, Chang CH, McNamara L, McKeever B, Mosley RT, Berger JP, Meinke PT

Benzimidazolones: a new class of selective peroxisome proliferator-activated receptor gamma (PPARgamma) modulators.

J Med Chem. 2011 Dec 22;54(24):8541-54. doi: 10.1021/jm201061j. Epub 2011 Nov 28.

PubMed ID

22070604 [ View in PubMed

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Abstract

A series of benzimidazolone carboxylic acids and oxazolidinediones were designed and synthesized in search of selective PPARgamma modulators (SPPARgammaMs) 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 PPARgamma full agonist drugs. Structure-activity relationships of these potent and highly selective SPPARgammaMs were studied with a focus on their unique profiles as partial agonists or modulators. A variety of methods, such as X-ray crystallographic analysis, PPARgamma transactivation coactivator profiling, gene expression profiling, and mutagenesis studies, were employed to reveal the differential interactions of these new analogues with PPARgamma 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-meth yloxazolidinedione (51) demonstrated efficacy equivalent to that of rosiglitazone. Side effects, such as fluid retention and heart weight gain associated with PPARgamma full agonists, were diminished with 51 in comparison to rosiglitazone based on studies in two independent animal models.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Rosiglitazone	Peroxisome proliferator-activated receptor gamma	EC 50 (nM)	200	N/A	N/A	Details
Rosiglitazone	Peroxisome proliferator-activated receptor gamma	EC 50 (nM)	30	N/A	N/A	Details
Rosiglitazone	Peroxisome proliferator-activated receptor gamma	EC 50 (nM)	46	N/A	N/A	Details
Rosiglitazone	Peroxisome proliferator-activated receptor gamma	EC 50 (nM)	110	N/A	N/A	Details