基于结构的新型PPARγ选择性调控剂靶向吲哚衍生物的设计、合成及其抗II型糖尿病作用机制探究

The incidence of type II mellitus (T2DM) is quickly emerging as a national medical concern with the lifestyle changing. The widespread prescription of PPARγ classical agonists, such as Actos and Avandia, has been prevented due to adverse effects including weight gain, edema, and increased risk of congestive heart failure. So far a lot of potent PPARγ modulators were reported, however, new safer PPARγ modulators are still far away from market due to lack of basic understanding of how PPARγ activation by ligands is linked with their anti-diabetic effects. Recently, we have discovered a new class of indole derivatives, as the selective PPARγ modulators, showed potent PPARγ activities in binding assays, selective regulation agonism in cell-based transactivation assays, obvious hypoglycemic effects and low inducing differentiation effects in adipogenesis assays. Notably, the crystal structure analysis of representative compounds (VSP-51 and VSP-51-2) and PPARγ complexes showed that such type of indole derivatives have a unique binding mode in the ligand binding pocket of PPARγ. Our preliminary results open a new window for mechanism study of ligand activation of PPARγ. Herein, we will based on the crystal structures of our developed indole derivatives and PPARγ complexes and the biological data of our developed indole derivatives as the selective PPARγ modulators as for the design and synthesis of new targeted indole derivatives with higher potency. These new indole derivatives will be useful chemical probes for uncovering the mystery of ligand modulated PPARγ activation. We will also optimize the pharmacokinetic profiles of new indole derivatives and evaluate their in vivo efficacy for the discovery of PPARγ-based orally anti-diabetic drugs with improved therapeutic profiles.

II型糖尿病(T2DM)已经成为严重影响我国人民健康的流行病。然而，现有针对PPARγ靶点开发的口服降糖药由于副作用，已经受到了限制使用。另外，由于小分子配体调控PPARγ功能机制不清楚，阻碍了近来开发的PPARγ调控剂作为降糖药物的发展。前期我们发现了一类新型吲哚类衍生物选择性调控了PPARγ生物学功能，从而产生了潜在的降糖效果、低的相关副作用。代表化合物（VSP-51和VSP-51-2）与PPARγ复合物晶体数据显示该类化合物以一种新型作用模式结合并调控PPARγ。这些前期结果为研究小分子调控PPARγ功能机制提供了新的思路。本项目将基于前期获得的吲哚衍生物与PPARγ晶体结构数据，系统设计、合成具有明显靶向特征的新型潜力吲哚类衍生物，为探索小分子配体调控PPARγ功能机制研究提供新型化学探针；评价及优化该类化合物的成药性，为发展高效安全的口服降糖药物提供候选化合物。

II型糖尿病(T2DM)已经成为严重影响我国人民健康的流行病。然而，现有针对PPARγ靶点开发的口服降糖药由于副作用，已经受到了限制使用。另外，由于小分子配体调控PPARγ功能机制不清楚，阻碍了近来开发的PPARγ调控剂作为降糖药物的发展。鉴于此，我们在该基金的资助下，通过与国内外相关课题组展开合作，取得了阶段性研究结果：（1）成功解析了VSP-77/PPARγ复合物晶体与VSP-51-2/PPARγ复合物晶体结构，并系统阐述了该类化合物与PPARγ的具体结合区域及精确作用位点 ；（2）基于结构的设计, 利用最近热门的过渡金属催化C-H活化策略高效合成了一系列具有明显靶向特征的新型VSP衍生物；（3）进一步体内外综合评估发现代表化合物VSP-77、VSP-51-2及抗菌药物-芬替康唑、抗血栓药物-双香豆素具有高效降糖、低副作用的潜力。该部分研究结果在Angew. Chem. Int. Ed.、Chem. Sci.、ACS Catal., Green Chem., Org. Lett.等知名杂志已发表SCI研究论文20篇; 申请国家发明专利4项，授权2项。该系列的成果为下一步的国家均有自主知识产权的抗II型糖尿病的创新药物设计与发现打下了坚实的基础。鉴于II型糖尿病在我国的流行性，因此该研究项目具有深远的社会意义和广阔的临床应用前景。可以预见，对该药物的成功研发，将会开创强效安全降糖的新时代，并因此带来巨大的经济效益及社会效益。