高效且具选择性的苄氧基苄基类过氧化物酶体增殖物激活受体 (PPAR) δ 激动剂的发现。
Discovery of highly potent and selective benzyloxybenzyl-based peroxisome proliferator-activator receptor (PPAR) delta agonists.
作者信息
Bratton Larry D, Filzen Gary F, Geyer Andrew, Hoffman Jennifer K, Lu Gina, Pulaski Jim, Trivedi Bharat K, Unangst Paul C, Xu Xiangyang
机构信息
Department of Chemistry, Pfizer Global Research and Development, Michigan Laboratories, Ann Arbor, MI 48105, USA.
出版信息
Bioorg Med Chem Lett. 2007 Jul 1;17(13):3624-9. doi: 10.1016/j.bmcl.2007.04.046. Epub 2007 Apr 24.
A series of 1,4-benzyloxybenzylsulfanylaryl carboxylic acids were prepared and their activities for PPAR receptor subtypes (alpha, delta, and gamma) with potential indications for the treatment of dyslipidemia were investigated. Analog 13a displayed the greatest binding affinity (IC(50)=10nM) and selectivity (120-fold) for PPARdelta over PPARalpha. Many of the analogs investigated were found to be highly selective for PPARdelta and were dependent on the point of attachment of the substituent. In the 1,4-series, analog 28e was found to be the most potent (IC(50)=1.7 nM) and selective (>1000-fold) compound for PPARdelta. None of the compounds tested showed appreciable binding affinity for PPARgamma.
制备了一系列1,4 - 苄氧基苄硫基芳基羧酸，并研究了它们对PPAR受体亚型（α、δ和γ）的活性，这些亚型具有治疗血脂异常的潜在指征。类似物13a对PPARδ显示出最大的结合亲和力（IC(50)=10nM），并且相对于PPARα具有选择性（120倍）。研究发现，许多所研究的类似物对PPARδ具有高度选择性，并且取决于取代基的连接点。在1,4 - 系列中，类似物28e被发现是对PPARδ最有效的（IC(50)=1.7 nM）和选择性最高的（>1000倍）化合物。所测试的化合物中没有一种对PPARγ显示出明显的结合亲和力。
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