基于天然骨架和药物片段构建新型ALR2抑制剂及抗炎作用研究

醛糖还原酶（ALR2）是糖尿病并发症药物研发的重要靶点，研究证明其在炎症相关疾病中也具有极其重要的作用。由于现有ALR2抑制剂（ARI）选择性低和药动性差，导致临床过敏和疗效问题，还未见FDA认可上市的ARI药物，因而研发新型ARI具有重要意义。在前期研究中，我们发现基于Curcumin骨架设计合成的类似物具有良好的ALR2抑制活性和抗炎作用；同时，在骨架类似搜索中，发现天然产物Agelastatin与临床III期Ranirestat母体相似，分子对接证明其对ALR2具有高度选择抑制作用。因此，本项目拟继续基于Curcumin类似物及Agelastatin骨架，引入ARI特征片段，通过分子模拟对接，设计、合成新型ARI小分子，研究其抑制作用、选择性及构效关系，不断优化分子结构，寻找新型ARI先导化合物，研究其抗炎作用及机理。本项目体现多学科交叉，可为研发新型ARI药物提供理论和实验依据。

Aldose reductase (ALR2) is one of the key targets for the research and development of the medicine of antidiabetic complications，and recent research demonstrated it played important roles to a number of inflammatory diseases. Because of current ARIs with low selective inhibition and poor pharmacokinetics, the problem of hypersusceptibility and low curative effect in clinic exists, no ARI is approved by FAD till now,therefore the research and development of new ARI is a need with great meaningful.In the previous Research, we found that the compounds, which were designed and synthesized using curcumin as template, exhibited potent ALR2 inhibitory and anti-inflammatory activities. Meanwhile, it was found that the skeleton of natural product ，Agelastatin， was similar to the structure of Ranirestat which is in the III clinic trials, and the molecular modeling and docking demonstrated that target moleculars exhibited high selective and inhibitory activities agaist ALR2. Therefore, this proposal plans to continously design and synthesize noval small moleculars, with computer aid, based on skeleton of Curcumin analogues or Agelastatin by inserting the characteric fragments of ARIs, study their inhibitory activities, selective inhibition and structure-activity relationship, and keep on optimizing the structure of moleculars till finding new lead compound, meanwhile study the anti-inflammatory activity and related mechanisms.This proposal presents the interdisciplinary combination, which will provide the theory instruction and experimental basis for research and development of new ARI drugs.