新型脂代谢调节分子胆汁酸-脂肪酸偶合物的设计、合成及作用机制研究

Lipid metabolism disorder is a serious threat to human health, there are currently no effective drugs to treat this disease. The fatty acid bile acid conjugates are a class of drugs with a novel mechanism of action on lipid metabolism, regulating cholesterol metabolism, preventing and treating atherosclerosis, nonalcoholic fatty liver, cholesterol gallstones, chemotherapy-related steatohepatitis. In this project, by coupling the fatty acid with bile acid using the biocompatible amino acids as connectors, we are to design and synthesize a class of novel fatty acid bile acid conjugates, to maximize the maintenance of the specific structure of the bile acid molecule, and to ensure the liver targeting compounds isotropic. Examine the effect of the connection location, connection groups, different types and conformation of amino acids on compound's activity and liver targeting and study on the mechanisms of regulating lipid metabolism so as to develop targeting drugs with stronger activity, being stable in plasma , effective transshipment into the liver, full dissociation in the liver to release active drug. In preliminary exploratory work of this project,we have found a new compound which shows slightly stronger activity in preventing and treating cholesterol gallstones, nonalcoholic fatty liver in an animal level than the positive drug. These results are initial proof of the rationality of our design and verification of the feasibility of this project. The implementation of this project will promote the development of therapeutic drugs on lipid metabolism disorders.

脂代谢紊乱严重威胁人类健康，目前尚没有有效的脂代谢调节药物。脂肪酸胆酸耦合物是一种作用机制新颖的脂代谢调节药物，具有调节胆固醇代谢，预防、治疗动脉粥样硬化、非酒精性脂肪肝、胆固醇结石、化疗相关脂肪性肝炎的作用。本项目通过改变脂肪酸与胆酸的偶合策略，以生物兼容性氨基酸为连接子，设计、合成一系列结构新颖的胆汁酸-脂肪酸偶合物，最大限度维持胆酸分子的特异结构，保证化合物的肝靶向性。考察偶合物连接位置、连接基团、氨基酸种类和构型对化合物活性和肝靶向性的影响，并研究目标化合物调节脂代谢的机理,研制活性更强、血浆中保持稳定、能有效转运进入肝脏、到达肝脏后能够解离、释放活性药物的靶向药物。本项目前期探索工作已经得到了1个动物水平对胆固醇结石、非酒精性脂肪肝预防、治疗活性略强于阳性药的化合物，初步证明了我们设计思想的合理性，验证了本项目的可行性。通过本项目的实施，将推进脂代谢紊乱治疗药物的发展。

脂代谢紊乱严重威胁人类健康，目前尚没有有效的脂代谢调节药物。脂肪酸-胆酸耦合物是一种作用机制新颖的脂代谢调节药物，具有调节胆固醇代谢，预防、治疗动脉粥样硬化、非酒精性脂肪肝、胆固醇结石、化疗相关脂肪性肝炎的作用。本项目通过改变脂肪酸与胆酸的偶合策略，以生物兼容性赖氨酸为连接子，设计、合成一系列结构新颖的胆汁酸-脂肪酸偶合物，最大限度维持胆酸分子的特异结构，保证化合物的肝靶向性。考察偶合物连接位置、连接基团、氨基酸种类对化合物活性和肝靶向性的影响，研制一系列活性更强、血浆中保持稳定、能有效转运进入肝脏、到达肝脏后能够解离、释放活性药物的靶向药物。本项目共合成27个新的脂肪酸-胆酸耦合物化和5个阳性对照药，通过详细的生物学和靶向性评价，发现3个苗头化合物I10、IIc 和IIg：其中I10 可以预防和减少胆结石的形成和/或脂肪肝，可以作为一种潜在的抗胆囊结石的候选治疗药物，对胆固醇结石、非酒精性脂肪肝预防、治疗活性略强于阳性药的候选化合物熊去氧胆酸；IIc 和IIg 是潜在的降血脂药物，对高脂饮食诱导的肝损伤具有肝细胞保护作用，降脂活性均显著强于阳性药Aramchol。证明了我们设计思想合理，实现本项目的预期。通过本项目的实施，推进脂代谢紊乱治疗药物的发展。