选择性磷酸二酯酶9型抑制剂的设计、成药性优化及抗肺纤维化作用研究

特发性肺纤维化是以肺间质纤维化为特征的致死性疾病，死亡率高于多种癌症，尚无理想治疗药物。新靶点/新机制药物研发成为该领域的重大挑战之一。我们近期发现磷酸二酯酶九型PDE9高选择性抑制剂1791的抗肺纤维化体内药效明显优于阳性药吡非尼酮，且类药性好，提示PDE9抑制剂有望成为全新机制的抗肺纤维化候选药物；并发现1791显著下调肺纤维化大鼠肺组织α-SMA、胶原及TGF-β蛋白表达水平，推测其抗肺纤维化药效与TGF-β介导的通路相关。然而该类化合物成药性有待提升。基于我们已获得的PDE9与1791共晶结构，本项目拟定向PDE9多个关键残基设计并合成100个目标化合物，系统研究构效关系；优选1-3个PDE9抑制活性强、亚型选择性高、成药性好、抗肺纤维化药效显著的先导物；探索抑制剂对靶蛋白的选择识别机制及对TGF-β/Smad通路的影响。本项目将为PDE9抑制剂作为抗肺纤维化新靶点药物提供理论依据

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive and deadly disease which is characterized by diffuse interstitial pulmonary fibrosis. The mortality rate of IPF is higher than many cancer. Existing drugs for IPF only alleviate or delay the progression of fibrosis. Development of drugs with novel target and mechanism is one of the big challenge in this area. Our recent studies demonstrated that highly selective PDE9 inhibitor 1791 with good physicochemical property, attenuated bleomycin-induced pulmonary fibrosis in rats, indicating that PDE9 may be a novel drug target for the treatment of IPF. Furthermore, we also found that administration of 1791 significantly attenuated the level of α-SMA, Col I and TGF-β1 in the lungs of rats, indicating that the anti-fibrosis effects of PDE9 inhibitors may be mediated by the TGF-β signaling pathways. However, the druggability of 1791 is still needed to be improved. Based on these results, in this project we are plan to design about one hundred novel compounds using the computer-aided drug design methods. After the organic synthesis of these compounds, we will choose one to three compounds with high inhibitory activity towards PDE9, high selectivity over other PDEs, good druggability as well as anti-fibrosis effects. Furthermore, we will explore the binding modes of PDE9 selective inhibitor with PDE9 protein using the crystal structures. We will also explore whether the anti-fibrosis effect of PDE9 inhibitors is mediated by TGF-β/Smad signaling pathway. This project will provide new evidences of PDE9 as a novel target for the treatment of idiopathic pulmonary fibrosis.