五环三萜类天然产物来源的法尼酯X受体调节剂的发现、优化与功能研究

Farnesoid X receptor (FXR), a nuclear receptor, has been regarded as a new and potential target for the treatment of diabetes and various metabolic diseases, and even cancer and infective diseases. FXR agonists have been actively pursued in the past decade, but few compounds entered clinic trials. This seemingly unsatisfactory results to the tremendous efforts on FXR agonists, as well as FXR antagonists which were only reported more recently, could be attributed to a lack of selectivity of FXR agonism or antagonism by these compounds on the regulation of thousands of genes that are modulated by FXR. Nowadays, it is recognized that seeking for FXR modulators which can selectively regulate down-stream genes should be a smarter choice. In the previous study, oleanolic acid (OA), a pentacyclic triterpene natural product, was found as selective FXR interacting agent with moderate activity. In this project, we will pursue more potent compounds through structure modification of OA and related compounds, assisted by structure-based design. In addition, such compounds are also expected to exhibit higher selectivity on FXR gene regulation. These novel FXR modulators will be tested for their anti-diabetic activity, as well as other potential uses. In addition, these compounds could also be used as tools to explore the gene regulation by FXR in depth.

法尼酯X受体（FXR）是一种可用于糖尿病和多种代谢性疾病、以及肿瘤和感染性疾病治疗的新型药物靶点。过去十多年人们对FXR激动剂进行了广泛探索，但仅有少数化合物进入临床试验。无论是对研究很多的FXR完全激动剂还是近几年才开始报道的FXR拮抗剂而言，对于数以千计受FXR调控的基因不能进行选择性激活或拮抗，是以FXR为靶的分子研究成果不理想的原因。现在人们认识到，寻找能对下游靶基因进行选择性调控的FXR调节剂应是一个更加明智的选择。前期工作中发现，五环三萜类化合物齐墩果酸（OA）是一个具有调节剂性质的中等活性的分子。本项目中通过基于结构的设计方法辅助OA及其相关物的结构修饰以增强活性，同时也希望从中发现可导致FXR调控基因的选择性更高的小分子。我们将考察这类新型FXR调节剂的抗糖尿病活性，并探索其它的潜在用途。此外，这类分子也能作为工具药，对FXR的基因调控进行更深入的研究。

法尼酯X受体（FXR）是一种用于糖尿病和多种代谢性疾病治疗的新型药物靶点，但FXR调控的基因不能被选择性激活或拮抗，在一定程度上制约着以FXR为靶的新药开发。本研究的主要目的是通过基于结构的设计方法，对五环三萜类化合物齐墩果酸(OA)进行结构修饰以增强活性，希望获得高活性的FXR调节剂，考察其抗糖尿病活性, 探讨其用于新药开发的潜力。.本项目研究中利用已报道的FXR配体与FXR共晶结构，构建五环三萜与FXR作用的分子模型，设计并合成了A环的C-3位和C环的C-11,12位结构修饰物，并利用FXRLBD-Gal4荧光素酶报告基因转染的哺乳动物单杂交细胞模型，检测了OA衍生物对FXR的作用。发现C-3衍生物对FXR未表现出明显的激动作用，以及对CDCA诱导的FXR激动的拮抗作用，但有部分化合物表现出弱的共激活作用。C-12位OA衍生物中作用优于C-3位，9个化合物表现出对GW4064激动FXR的拮抗活性，其中以代号为YMY-3-35的化合物拮抗活性最强，IC50为7.2 μM。对YMY-3-35的体内研究结果表明，该化合物200 mg/kg口服单次给药具有适宜的药代动力学性质，在此剂量下可显著降低自发性2型糖尿病KKAy小鼠的随机血糖、空腹血糖，改善葡萄糖耐受性，提高胰岛素敏感性，并可有效的控制小鼠血糖水平。机理研究中发现YMY-3-35可以降低FXR靶基因CYP7A1和BSEP、略微降低SHP、降低糖异生相关基因G6Pase。.综上所述，本项目研究结果表明，OA的结构改造对以FXR为靶开发降糖药物具有一定的意义，其中有的衍生物具有作为抗糖尿病先导化合物开发的价值。.