靶向PDE4的新型抗抑郁药物的设计、合成与作用机制研究

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.

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。

抑郁症是最常见的致残和危及生命的精神疾病之一，发病率很高，常伴有神经炎症和认知功能障碍。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，设计合成五个系列共152个新型化合物库，并分别在分子水平、细胞水平以及动物水平上完成了其药效评价。.基于此化合物库，本项目发现了许多具有进一步开发潜力的新型PDE4抑制剂：1）能快速穿过大脑屏障且具有神经保护作用的联二苯类PDE4抑制剂BIPA29；2）具有良好生物利用度（F = 42.96%），在口服剂量低于625mg/Kg时显示出良好的安全性，在5 mg/Kg剂量下无致呕吐潜能副作用，在1 mg/Kg剂量下显示良好改善认知作用与抗抑郁作用的新型氨基苯基酮类PDE4抑制剂Z19153；3）具有良好神经保护作用，抗神经炎症作用且能效降低小鼠脑部AChE活力的新型茚酮类PDE4/AChE双靶点抑制剂Z20252；4）毒性低且对神经细胞显示出良好保护作用的新型苯并恶唑类PDE4抑制剂Z22428。其中，PDE4抑制剂Z19153（专利ZL 202011057788.1）已转让给广州白云山制药股份有限公司进行后续开发。.综上所述，本项目发现了具有开发潜力的新型PDE4抑制剂Z19153、Z20252以及Z22428，其后续研究将有望发现靶向PDE4具有较好成药性可能的新型抗抑郁药物。