基于结构的新型选择性GR调控剂氢化可的松衍生物的设计、合成及其抗炎机制研究

Glucocorticoids as the most potent and effective agents for treating inflammation diseases are widely used in the drug market. However, even if at therapeutic dosages, glucocorticoids induce a range of debilitating side effects, including adiposity, diabetes, osteoporosis and skin atrophy et al. Therefore, the discovery and development of novel synthetic glucocorticoids, which retain their beneficial therapeutic effects but reduce adverse side effects, is still a major medical challenges. Over the past several years, an understanding of the molecular mechanisms by which corticosteroids exert their biological effects has begun to emerge. The action of glucocorticoids is mediated through the glucocorticoid receptor (GR), and GR regulates gene expression either by transcriptional activation (transactivation) or by transcriptional repression (transrepression). The transrepression activity of GR is considered to be the major basis for the anti-inflammatory and immunosuppressive effects of glucocorticoids，and the transactivation is considered to be associated with steroid side effects. However, the certain molecular mechanisms of transrepression and transactivation of the glucocorticoid pathway has not yet been clearly explained. In our present program plan, based on the crystal structures of GR and dexmethaone, deacylcortivazol, cortisol or mometasone furoate, using the method of computer-aided drug design, a series of hydrocortisone derivatives by using VSG-22 as the mother nucleus will be designed, synthesized and evaluated with the aim to obtain the selective GR modulators. Besides, the molecular mechanism and pharmacokinetics of obtained compounds should also be investigated. Moreover, the selected hydrocortisone derivatives will be evaluated concerning the anti-inflammatory activities, side-effects and preliminary toxicities in vivo. Finally, several superior anti-inflammatory agent will be obtained with a reduced iatrogenic profile. Our work provides a substantial basis for the discovery of structurally novel glucocorticoids that can make distinction between transcriptional repression and activation pathways.

糖皮质激素类化合物作为当今最有效的抗炎症药物已经广泛的应用于市场中。然而，即使其以监管标准剂量长期使用也会导致肥胖症、糖尿病和骨质疏松等多种副作用。因此，研发具有强疗效、低副作用的糖皮质激素类药物仍是该领域中的一项巨大挑战。目前研究表明：糖皮质激素主要通过两种路径发挥作用，包括转录抑制路径（TR）和转录激活路径 (TA)。TR路径是这类药物在生物体内产生抗炎和免疫抑制作用的主要依据；而TA路径是导致多种严重副作用的重要原因。但是TR和TA路径的具体分子机制尚未清楚。本项目将以糖皮质激素受体复合物晶体结构为基础，以前期工作中获得的VSG-22为模板，通过计算机辅助药物设计的方法，设计并合成一批具有选择性、强抗炎活性的氢化可的松衍生物，即通过化学修饰方法选择性激活TR路径；并对活性较好的化合物进行抗炎分子机制、体内外药代及药效研究，为进一步研究开发糖皮质激素类抗炎药物打下基础。

糖皮质激素受体(Glucocortiucoids receptor，GR)是一个开发抗炎药物的热门靶标。至今，以其为靶点开发的糖皮质激素类药物已作为当今最有效的抗炎药物而被广泛地应用于市场中。然而大量的临床实验表明：糖皮质激素类药物具有非常大的副作用，即使其以监管标准剂量长期使用仍然会导致肥胖症、糖尿病、骨质疏松、皮肤萎缩等多种副作用。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）成功解析了皮质醇(Cortisol)/GR复合物晶体与糠酸莫米松(MF)/GR复合物晶体结构，并系统阐述了该类糖皮质激素与GR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氢化可的松衍生物；（3）进一步体内外综合评估发现代表化合物VSG-22、VSG-C12、VSG-158具有高效抗炎、低副作用的潜力。该部分研究结果在Org. Lett.、ACS Catal.等知名杂志已发表SCI研究论文14篇, 另外一篇文章在PNAS杂志正在修改当中; 并转让该项目相关的PCT专利一项，转让总金额为784万美元。该系列的成果为下一步的国家均有自主知识产权的抗炎尤其抗哮喘创新药物设计与发现打下了坚实的基础。鉴于哮喘在我国的流行性，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，将会开创强效炎症抑制药物的新时代，并因此带来巨大的经济效益及社会效益。