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

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