磷酸二酯酶五型(PDE5)抑制剂广泛临床用于肺动脉高压(PAH)治疗，但其因亚型选择性低而导致产生诸多副作用。因此，提高抑制剂选择性成为PDE5研究亟需解决的关键科学问题。项目组近期发现的吡咯色原酮类PDE5高活性抑制剂1607，与阳性药西地那非相比，具有骨架结构新颖、选择性更高及抗PAH体内药效更显著等特点(JMC2017)。共晶结构发现该类抑制剂可伸入PDE5的Q2口袋，具有不同于西地那非的作用机制。但该抑制剂对部分PDE亚型的选择性和溶解度尚不理想。.在已有基础上，本项目拟定向Q2口袋多个重要残基，使用多种药物设计方法，设计合成新型吡咯色原酮类化合物，综合其对PDE5抑制活性、PDE各亚型选择性、抗PAH药效并优化类药性，发现1-3个优选化合物；开展优选化合物与靶标的相互作用研究，以阐明PDE5识别选择性抑制剂的分子机制。本项目将为研发自主知识产权抗PAH创新药物提供先导化合物储备。

Phosphodiesterase 5 (PDE5) inhibitors have been used as clinical agents for treatment of pulmonary arterial hypertension (PAH), but the defects of low selectivity for its inhibitors caused many side effects. Therefore, the discovery of highly selective inhibitors has become the key problems which need to be solved urgently in PDE5 research. Recently, we constructed a PDE5 inhibitor entity library with a skeleton of 1-arylchromeno[2,3-c]pyrrol-9(2H)-one. Compared with the reference drug sildenafil, the lead compound 1607 gave a different skeleton structure and equivalent anti-PAH efficacy, but higher selectivity and exhibits excellent pharmacokinetic properties. Crystal structure show that these 1-arylchromeno[2,3-c]pyrrol-9(2H)-ones can entered into the Q2 pocket of PDE5, while sildenafil did not show this feature. Both gave different binding patterns and molecular mechanisms. However, the compound 1607 only have moderate selectivity index versus subtypes (PDE2/6/10) and poor water solubility. In this study, we will design and synthesize of new series of 1-arylchromeno[2,3-c]pyrrol-9(2H)-ones and take into full consideration of the important residues in the Q2 pocket. In view of their PDE5 inhibitory activity, selectivity index versus other PDE subtypes, pharmacodynamics of PAH, and safety properties, we will select 1-3 leads. Then we will obtain the crystal structures of PDE5 in complexes with the leads to identify the important residues which affect the selectivity of inhibitors. This project will elucidate the molecular recognition mechanism of PDE5 selective inhibitors and provide more scientific basis for the design of highly selective inhibitors against PDE5.