肺动脉高压(PH)是一种高致死率的恶性肺血管疾病，发展新型安全有效的PH药物具有重要意义。本课题基于PDE5抑制剂及NO分子通过调控NO-sGC-cGMP发挥治疗作用的有效性，首次提出“设计双功能的NO供体型PDE5抑制剂通过协同作用来提高肺血管的舒张反应并抑制肺血管重构，进而治疗PH疾病”的策略。通过对结构片段的虚拟筛选、优化组合和精细调控，拟构建以生物活性为导向的多样性PDE5抑制剂–NO供体偶联化合物库，协同调控NO通路，产生联合作用实现增强PH治疗的有效性、避免耐药性的目标。进一步在酶学、细胞和组织水平上系统评价化合物通过抑制PDE5活性、补充外源性NO，有效舒张肺血管的治疗潜力，并采用PH大鼠模型探索其治疗作用，最终获得3–5个在活性、选择性及成药性三方面均最佳的先导化合物或候选药物分子。形成运用PDE5抑制剂–NO供体偶联药物治疗PH的关键技术平台，为发现新型PH药物奠定基础。

Pulmonary hypertension (PH) is a chronic and progressive cardiovascular disease that is associated with significant morbidity and mortality. Therefore, development of novel drugs for the treatment of PH is still of great importance. Targeting NO-sGC-cGMP signaling pathway by using phosphodiesterase type 5 inhibitor (PDE5i) and inhaled nitric oxide (iNO) have been proved to be effective in PH patients. For the purpose of discovering novel therapeutics for pulmonary hypertension with higher potencies and less side-effects, we proposal that constructing bifunctional NO–releasing PDE5 inhibitor is an alternative approach for the treatment of PH by increasing vasorelaxant effects and preventing pulmonary vascular remodeling. According to fragment-based in situ screening, structure-based optimization and comprehensive medicinal chemistry, a small molecule library of PDE5i–NO donor hybrids will be synthesized with a variety of tadalafil derivetives/Linker/NO donor structures. According to the multiple functions of the structure fragments, the hybrids could take advantages of lung-targeting therapy and synergistic effect in modulating NO related signaling, which contribute to both the increase of potency and inhibition of drug-resistance. By the hierarchical multiple-filter in vitro evaluation strategy, the PDE5 inhibitory potencies, NO releasing abilities and vasodilatory effects of these compounds would be well established for estimating their therapeutic potentials for PH. Based on the in vivo efficacy of the NO–releasing PDE5 inhibitor prevents the development of monocrotaline-induced PH in rats, 3–5 lead compounds/drug candidates will be finally obtained with optimized potency, selectivity and drug-like properties. This work will establish the novel strategy that using PDE5i–NO donor hybrids to modulate PH progress, and contribute to the further drug discovery of novel PH therapeutics.