基于吸入一氧化氮（NO）气体治疗肺动脉高压（PAH）的临床实践以及齐墩果酸衍生物CDDO-Me有效干预PAH的临床研究结果，本项目提出应用具有舒张血管和抑制血管重构双重作用的药物治疗PAH新策略，设计、合成NO供体型CDDO-Me衍生物I-III，通过雾化吸入给药使其主要分布在肺组织，并在该组织中高表达的赖氨酰氧化酶等作用下释放CDDO-Me和NO。NO产生舒张肺动脉血管活性；CDDO-Me主要抑制NF-κB，激活Nrf2通路，抗炎、抗氧化，发挥抑制肺动脉血管重构的作用。项目研究内容还包括：I-III的雾化剂处方筛选，测定NO释放，评价其对肺动脉平滑肌细胞和肺动脉内皮细胞的影响，研究活性化合物体内组织分布以及体内抗PAH活性，考察其安全性，并从细胞、分子水平上探索其作用机制。本项目的成功实施可为NO供体药物局部给药提供新的思路，同时也为发现新型抗PAH候选新药打下良好的基础。

In this project, based on the extensive clinical practice using inhaled nitric oxide for the treatment of pulmonary arterial hypertension (PAH) and the disclosed phase II results for Bardoxolone Methyl (CDDO-Me) treatment in patients with PAH, a new therapeutical concept, that is combination of pulmonary arterial vasodilatation and vascular remodeling inhibition, is proposed. In this regard, three groups of NO-donating CDDO-Me derivatives (I-III) have been designed and will be synthesized. After inhaled, I-III could mainly distribute in lung tissue, and be decomposed in the presence of lysyl oxidase (LOX), which is over-expressed in lung tissue of PAH patients, to NO and CDDO-Me, generating pulmonary arterial vasodilatation effects as well as antiimflammatory, antioxidative, and vascular remodeling inhibitory activities via inhibition of NF-κB and activation of Nrf2 pathway. Notably, the inhalation administration could avoid the NO release in other tissues or organs, lowering the undesired side effects and thus improving the druggability. The detailed study items include: aerosol formulation study, in vitro NO release study, inhibitory effect against pulmonary artery smooth muscle cells growth and protection effect on pulmonary artery endothelial cells, in vivo tissue distribution investigation, in vivo anti-PAH evaluation, mechanism studies in cell and molecule levels. This project could give a good example for topical administration-based NO-donating drug development, as well as one or two NO-donating candidates with potential intervention of PAH.