抑郁症是发病率极高的神经精神疾病之一，常伴随有神经炎症与认知障碍。而且重度抑郁症易导致自杀。然而现有抗抑郁药物起效慢，且长期服用后具有严重毒副作用。磷酸二酯酶4（PDE4）在中枢神经系统中起着重要作用，其抑制剂的良好抗抑郁、改善认知以及抗神经炎症作用为抑郁症提供了一个全新的治疗策略。基于前期研究发现的具有良好抗抑郁与抗神经炎症作用的选择性PDE4抑制剂FCPR03与FCPR16，本项目在深入了解PDE4与小分子结合模式基础上，结合经典药物设计与现代药物设计方法对其结构进行优化，设计合成结构新颖的选择性PDE4抑制剂。然后在分子水平、细胞水平以及动物水平上整体评价化合物的酶抑制活性与选择性，初步评价抗抑郁、改善认知以及抗神经炎症活性，对高活性化合物进行初步药代动力学、急性毒性与副作用的成药性评价，研究优势化合物的作用机制。本项目的实施将有望发现靶向PDE4具有较好成药性可能的新型抗抑郁药物。

Depression is one of the most common disabling and life-threatening psychiatric disorders with very high incidence, accompanied by neuroinflammation and cognitive dysfunction. Moreover, major depression may lead to suicide. However, listed antidepressants reveal some shortcoming, such as slow effect, serious side effect after long-term use. Phosphodiesterase IV (PDE4) plays an important role in the central nervous system, and its inhibitors with good anti-depression, cognition enhancement, and anti-neuroinflammation activities represent a novel therapeutic strategy for central nervous system (CNS) disorders, such as depression. Our previous studies demonstrated that compounds FCPR03 and FCPR16 were selective PDE4 inhibitors with good anti-depression, and anti-neuroinflammation activities. Depression is one of the most common disabling and life-threatening psychiatric disorders with very high incidence, accompanied by neuroinflammation and cognitive dysfunction. Moreover, major depression may lead to suicide. However, listed antidepressants reveal some shortcoming, such as slow effect, serious side effect after long-term use. Phosphodiesterase IV (PDE4) plays an important role in the central nervous system, and its inhibitors with good anti-depression, cognition enhancement, and anti-neuroinflammation activities represent a novel therapeutic strategy for central nervous system (CNS) disorders, such as depression. Our previous studies demonstrated that compounds FCPR03 and FCPR16 were selective PDE4 inhibitors with good anti-depression, and anti-neuroinflammation activities. Therefore, based on the binding model of PDE4 and their inhibitors, a combination approach of classical drug design and modern drug design techniques is applied to design new PDE4 inhibitors, using selective PDE4 inhibitors FCPR03 and FCPR16 as lead compounds. These synthesized compounds are assayed for their inhibitor activities, selectivity, anti-inflammatory activities, the antidepressant activities and cognition enhancement at molecular, cellular and animal levels. Those compounds with higher activities are further evaluated on their pharmacokinetics, acute toxicity, and emesis properties. Finally, the privileged compounds are selected to explore their mechanism of action. Therefore, the implementation of this project would be expected to develop new anti-depressant drug targeting PDE4 with better therapeutic profiles.