激活AMPK通路并促进脂肪细胞棕色化的抗肥胖症先导化合物发现及作用机制研究

In view of a surge in obesity group and handful of effective antiobesity drugs, research and development of antiobesity new drugs are very important. AMPK pathway is closely related to development of obesity, is considered to be promising targets for antiobesity drugs. And to promote the adipocytes browning become a new direction in the field of obesity treatment. Our previous studies have found that natural product bouchardatine and its derivatives had obvious lipid-lowering activity, and they work through the activation of AMPK pathway (ACS Chem Biol, 2013, BMC 2015, JMC 2015). Our latest study showed that compounds could also promote the adipocytes browning and increase the energy consumption, which indicate the possible relationship between AMPK activation and adipocytes browning. Thus the applicant propose a new strategy of antiobesity drugs research based on activating AMPK pathway and promoting adipocyte browning. In this research, on the basis of our previous research results, we will set up new screening systems, design，synthesize, and screen a series of new small molecules, summarize the structure-activity relationshuip, deeply explore the relationship between AMPK pathway activation and adipocytes browing, reveal the molecular mechanism and possible target of compounds against obesity, identify lead compounds with high activity and good druggability for antiobesity. This project might provide a useful theoretical and experimental basis for the establishment of new therapy strategy and the development of new anti-obesity drugs.

当前全球肥胖症人数剧增而有效药物匮乏，因此，抗肥胖症新药研究意义重大。AMPK通路失活与肥胖症发生发展密切相关，而促进脂肪细胞棕色化是肥胖症治疗领域的新方向。申请人前期发现，天然产物bouchardatine及其衍生物具有明显降脂活性，其通过激活AMPK通路发挥作用（ACS Chem Biol 2013, BMC 2015, JMC 2015）；最新发现该类化合物同时能促进脂肪细胞棕色化，提示AMPK通路激活和脂肪细胞棕色化之间可能密切相关。为此申请人提出了基于激活AMPK通路并促进脂肪细胞棕色化的抗肥胖症药物研究新策略。本项目将在前期工作基础上，构建新的筛选体系，设计、合成并筛选新化合物，总结构效关系，深入探究AMPK通路激活与棕色化之间的内在联系，阐明化合物体内外作用机制和可能靶点，发现活性高、成药性好的抗肥胖症先导化合物。为发展抗肥胖症治疗新策略和发现抗肥胖症新药提供理论和实验依据。

当前全球肥胖症人数剧增而有效药物匮乏，因此，抗肥胖症新药研究意义重大。AMPK通路失活与肥胖症发生发展密切相关，而促进脂肪细胞棕色化是肥胖症治疗领域的新方向。申请人前期发现，天然产物bouchardatine及其衍生物具有明显降脂活性，其通过激活AMPK通路发挥作用；最新发现该类化合物同时能促进脂肪细胞棕色化，提示AMPK通路激活和脂肪细胞棕色化之间可能密切相关。为此申请人提出了基于激活AMPK通路并促进脂肪细胞棕色化的抗肥胖症药物研究新策略。本研究主要开展了以下研究内容并取得了重要结果：（1）结合经典的高脂饮食诱导肥胖小鼠模型深入研究了Bouchardatine的体内外抗肥胖症活性与分子作用机制。（2）以Bouchardatine结构为基础，分别从A、B、C、D四个环系、醛基取代、侧链引入等方面，共设计合成了300余个新化合物，构建了Bouchardatine衍生物库；基于3T3-L1脂肪细胞筛选模型，筛选并评价了化合物的降脂活性，总结了构效关系；以代表性化合物为分子工具进一步研究了化合物体内外降脂/抗肥胖症作用机制。（3）深入探究了先导化合物R17和SYSU-3d的抗肥胖症及其并发症NAFLD/NASH作用的分子机制。研究发现，该类化合物可作为一类代谢调节剂，通过抑制ATP合成酶活性，降低组织细胞中ATP含量，提高AMP/ATP比值，从而激活LKB1-AMPK通路，并促进肝细胞脂质氧化分解代谢；LKB1可能是新的白色脂肪组织棕色化调节因子。本研究为基于能量代谢调控新机制的抗肥胖症及其并发症的创新药物研究奠定了基础。