新型磷酸二酯酶PDE1选择性抑制剂的发现、成药性优化和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，尚无理想治疗药物。新靶点/新机制药物是抗肺纤维化药物的重点研发方向之一。我们预实验发现：磷酸二酯酶PDE1高选择性抑制剂1921的抗肺纤维化体内外药效明显优于阳性药吡非尼酮，且类药性好，提示PDE1抑制剂有望成为一类全新机制抗肺纤维化候选药物；还发现1921显著下调肺纤维化大鼠肺组织α-SMA、胶原及TGF-β蛋白的表达水平，但该类化合物成药性有待提升。.在前期基础上，本项目拟采用药物分子设计技术，定向多个PDE1关键氨基酸设计并合成目标化合物库；综合其对PDE1抑制活性、PDE各亚型选择性、成药性和体内外药效等，获得2-3个性质均优的先导化合物。探索抑制剂对cAMP/cGMP相关通路、TGF-β/Smad通路的影响；深入研究抑制剂与靶标相互作用，阐明抑制剂特异性识别PDE1的分子机制。本项目为发现抗肺纤维化新策略/新机制药物提供理论依据。

Idiopathic pulmonary fibrosis (IPF) has the characteristics of high mortality and poor prognosis. There is no ideal treatment drug. New target / new mechanism drugs are one of the key research directions of anti-IPF drugs. In our preliminary experiment, we found that PDE1 highly selective inhibitor 1921 had better effects on pulmonary fibrosis than bifenidone in vitro and in vivo, which indicated that PDE1 inhibitors might be a new mechanism of anti-IPF candidates, and it was found that 1921 significantly reduced the expression of α-SMA, collagen and TGF-β protein in pulmonary tissue of rats with pulmonary fibrosis..On the basis of the earlier stage, the project plans to design and synthesize the target compound library by using the drug molecular design technology, targeting multiple key amino acid residues of PDE1; by integrating its inhibition activity to PDE1, the selectivity of each subtype of PDE, druggability, and in vitro and in vivo efficacy, to discover 2-3 compounds with excellent properties. To explore the effect of inhibitors on the cAMP /cGMP and TGF-β/Smad pathway; to further study the interaction between inhibitors and targets, and to clarify the molecular mechanism of specific recognition of PDE1 by inhibitors. This project provides theoretical basis for the development of new anti-fibrosis strategies / new mechanism drugs.