PDE4是当前备受关注的抗COPD药物新靶标，但其抑制剂因选择性低导致诸多副作用，发现高选择性抑制剂已成为PDE4药物研究亟需解决的关键科学问题。我们发现具有全新骨架结构的天然产物Selaginpulvilin K对PDE4有较高的抑制活性和选择性，是目前文献报道活性最强的天然PDE4抑制剂；还获得其与PDE4的共晶结构，揭示其全新的作用机制及影响活性的关键结构要素。我们还对该类骨架进行了初步全合成并获得少量化合物，发现其存在溶解性差等问题。本项目在已有工作基础上，拟：1）采用多种药物设计方法，针对Selaginpulvilin K多个可修饰区域，设计合成系列衍生物；2）测试其对PDE4的抑制活性、选择性，优选出具有较高生物利用度的nM级先导化合物；3）开展先导化合物与PDEs的相互作用研究，阐明PDE4识别选择性抑制剂的分子机制，为设计高选择性PDE4抑制剂提供更为充分的科学依据。

Phosphodiesterase-4 (PDE4) has been paid much attention as a novel target for anti-COPD (Chronic obstructive pulmonary diseases) drugs, but the defects of low selectivity for its inhibitors severely limits the application in clinical research. Therefore, the discovery of highly selective inhibitors has become the key problems which need to be solved urgently in PDE4 drug research. We have first reported that the novel natural product Selaginpulvilin K first isolated from Selaginella pulvinata has good PDE4 inhibitory activity and PDE subtypes selectivity. Meanwhile, we have obtained the crystal structures of PDE4 in complexes with Selaginpulvilin K to identify important residues which affect the selectivity of inhibitors. In the present project, targeting the important residues in the active pocket, we will design and synthesize new series of Selaginpulvilin derivatives. In view of their inhibition on PDE4 inhibitory activity, PDE subtypes selectivity and bioavailability, we will select 1-3 leads with nM level. This project will elucidate the molecular recognition mechanism of selective inhibitors of PDE4, and provide more scientific basis for the design of highly selective PDE4 inhibitors.