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

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

Authors :
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
Source :
Journal of medicinal chemistry [J Med Chem] 2011 Dec 22; Vol. 54 (24), pp. 8541-54. Date of Electronic Publication: 2011 Nov 28.
Publication Year :
2011

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.

Details

Language :
English
ISSN :
1520-4804
Volume :
54
Issue :
24
Database :
MEDLINE
Journal :
Journal of medicinal chemistry
Publication Type :
Academic Journal
Accession number :
22070604
Full Text :
https://doi.org/10.1021/jm201061j