磷酸二酯酶4（PDE4）是抗抑郁的有效靶点，但其抑制剂因亚型选择性低而易导致副反应，严重限制了该类药物的临床应用。高亚型选择性抑制剂的开发已成为PDE4研究领域亟需解决的关键科学问题。前期工作发现，异橙酮类天然产物臀腺素等具有一定PDE4抑制活性。基于此，申请人发展了该类化合物的高效合成方法，并得到更优抑制活性和选择性的衍生物Y43。同时，获得并解析了其与PDE4D催化域的共晶结构，了解了作用模式。本项目拟在已有基础上，运用计算机辅助药物设计、片段拼合等策略对Y43进行优化和改造，设计合成一系列高活性、高选择性的新型PDE4D抑制剂；培养优选化合物与PDE4D蛋白的共晶，阐明其与酶的的分子作用机制；测试优选化合物的细胞毒性、肝微粒体代谢稳定性及抗神经炎症活性；评价优选化合物的抗抑郁药效及致呕效应。本项目有望发现靶向PDE4D的新型抗抑郁先导化合物，为该类抑制剂的研发提供更充分的科学依据。

Phosphodiesterase 4 (PDE4) is an effective target for the treatment of depression, however, the defects of low subtype selectivity for its inhibitors caused many side effects and severely limits their clinical application. Therefore, the development of highly subtype selective inhibitors has become the key scientific problems, which need to be solved urgently in the field of PDE4 research. Our recent work shows that the natural product marginalin and isoaurostatin exhibit good PDE4 inhibitory activity. Subsequently, a new efficient synthetic route has been developed, and a better inhibitory activity and selectivity derivative Y43 was then obtained. Furthermore, the co-crystal of Y43 with human PDE4D catalytic domain were obtained and elucidated, confirming the information about inhibitor−enzyme interactions. In the present project, a series of novel PDE4D inhibitors with high activity and selectivity using computer-aided drug design, fragment assembly and other strategies will be designed and synthesized based on existing research. Then, the co-crystals of preferred compound and PDE4 will be obtained to elucidate the molecular recognition mechanism. Meanwhile, the cytotoxicity, metabolic stability and anti-neuroinflammatory activity in vitro of the selected compounds will be tested. Finally, the antidepressant efficacy and emetic potential will be evaluated in vivo. This project is expected to discover novel antidepressant lead compounds targeting PDE4D, and provide more scientific basis for the design of highly selective PDE4D inhibitors.