用于治疗2型糖尿病的PPARα/γ双重激动剂的设计、合成与生物活性研究

过氧化物酶体增殖因子活化受体（peroxisome proliferators activated receptor,PPAR）属于核受体超家族，与许多代谢疾病，如糖尿病、脂质异常、肥胖以及动脉粥样硬化等有关。已报道的PPAR受体共有三种亚型：α、β（或σ）以及γ。PPARα激动剂（如贝特类药物）可以降血脂；PPARγ激动剂（如格列酮类药物）可以增加胰岛素敏感性，但存在肝毒性、体重增加等副作用。新型的PPARα/γ双重激动剂可以保持PPARγ激动剂的降糖作用，并且通过激活PPARα受体达到减少PPARγ激动剂副作用的目的。本项目利用计算机辅助药物设计的方法对前期研究的茚酮类化合物（1）进行结构改造，设计并合成一类PPARα/γ双重激动剂，利用体外生物活性实验分别测定化合物对两种受体亚型的激动活性，并利用动物模型测定降糖及降脂活性，在活性基础上建立构效关系。

Peroxisome proliferators activated receptors (PPARs) are a kind of nuclear receptors and they play a crucial role in metabolic regulation of glucoses, lipids and cholesterols, and now they have been important therapeutic targets for metabolic syndrome (MS). PPARs include three subtypes, i.e. α、β/δ and γ. PPARα agonists (fibrates) are effective hypolipidemic agents and PPARγ agonists (thiazolidinediones TZDs) improve insulin sensitivity. However, edema, weight gain, and hepatotoxicity have been reported in patients after treatment with PPARγ agonists. It was suggest that the side effect of the body weight increase accompanied by PPARγ agonists may not be associated with PPARα/γ dual agonists. The indenones which were researched in the past are modified and optimized by computer aided drug design (CADD) and a novel serie as PPARα/γ dual agonists are designed and will be synthesized. The activites of all target chemicals will be evaluated by models in vivo and in vitro. Based on the agonistic activity, the structure-activity relationship will be investigated to provide more scientific evidences for PPARα/γ dual agonists for the treatment of type 2 diabetes.