Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, United States.
J Med Chem. 2011 Dec 22;54(24):8541-54. doi: 10.1021/jm201061j. Epub 2011 Nov 28.
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.
我们设计并合成了一系列苯并咪唑酮羧酸和恶唑烷二酮，以期寻找选择性过氧化物酶体增殖物激活受体γ（PPARγ）调节剂（SPPARγMs），作为治疗 2 型糖尿病（T2DM）的潜在治疗药物，与目前市售的 PPARγ 全激动剂药物罗格列酮和吡格列酮相比，具有更好的安全性。我们研究了这些强效且高度选择性的 SPPARγMs 的构效关系，重点研究了它们作为部分激动剂或调节剂的独特特性。我们采用了多种方法，如 X 射线晶体学分析、PPARγ 转录激活共激活因子分析、基因表达谱分析和突变体研究，以揭示这些新类似物与 PPARγ 受体的差异相互作用，与全激动剂相比。在 T2DM 的啮齿动物模型中，苯并咪唑酮类似物如（5R）-5-（3-[[3-（5-甲氧基苯并异恶唑-3-基）苯并咪唑-1-基]甲基]苯基）-5-甲基恶唑烷二酮（51）的疗效与罗格列酮相当。与罗格列酮相比，51 在两个独立的动物模型研究中，与 PPARγ 全激动剂相关的副作用，如液体潴留和心脏重量增加，有所减轻。
