A series of nitrogen heterocycles containing α-ethoxyphenylpropionic acid derivatives were designed as dual PPARα/γ agonist ligands for the treatment of type 2 diabetes (T2D) and its complications. 6-Benzoyl-benzothiazol-2-one was the most tolerant of the tested heterocycles in which incorporation of O-methyl oxime ether and trifluoroethoxy group followed by enantiomeric resolution led to the (S)-stereoisomer 44 b displaying the best in vitro pharmacological profile. Compound 44 b acted as a very potent full PPARγ agonist and a weak partial agonist on the PPARα receptor subtype. Compound 44 b showed high efficacy in an ob/ob mice model with significant decreases in serum triglyceride, glucose and insulin levels but mostly with limited body-weight gain and could be considered as a selective PPARγ modulator (SPPARγM).

中文翻译：

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6-苯甲酰基-苯并噻唑-2-酮骨架对α-烷氧基苯基丙酸衍生的PPAR激动剂药理作用的影响。

设计了一系列含有α-乙氧基苯基丙酸衍生物的氮杂环化合物作为PPARα/γ双重激动剂配体，用于治疗2型糖尿病（T2D）及其并发症。6-苯甲酰基-苯并噻唑-2-酮是最宽容的测试杂环，其中O-甲基肟醚和三氟乙氧基的结合以及对映体拆分导致（S）-立体异构体44b表现出最佳的体外药理学特性。化合物44b对PPARα受体亚型起非常有效的全PPARγ激动剂和弱的部分激动剂的作用。化合物44b在ob / ob小鼠模型中显示出高功效，其血清甘油三酸酯，葡萄糖和胰岛素水平显着降低，但大部分体重增加有限，可以被认为是选择性PPARγ调节剂（SPPARγM）。