双重食欲素受体拮抗剂类催眠药物的结构优化策略

Structure optimization strategy of dual orexin receptor antagonist hypnotic drugs

食欲素受体拮抗剂,特别是双重食欲素受体拮抗剂(DORAs),具有良好的镇静催眠效果,是近十年来新型镇静催眠药物研发的重点方向。较为经典的DORAs类药物有阿莫伦特、苏沃雷生、莱博雷生、达利多雷生等,DORAs类药物大部分是以U型分子骨架为基础对骨架上的模块进行改造,结构改造的核心目标是提高拮抗活性,此外还包括降低亲脂性、降低酶的时间依赖性抑制、降低药物外流比、提高脑浓度及降低P-糖蛋白的易感性。

Orexin receptor antagonists,especially double orexin receptor antagonists(DORAs),have good sedative and hypnotic effects,and have been the focus of research and development of new sedative and hypnotic drugs in the past decade.Classic DORAs include almorexant,suvorexant,lemborexant,daridorexant,etc.Most of DORAs modify modules on the skeleton based on U-type molecular skeleton,and the core goal of structural modification is to improve antagonistic activity.In addition,it also includes reducing lipophilicity,reducing time-dependent inhibition of enzymes,reducing drug outflow ratio,increasing brain concentration,and reducing the susceptibility to P-glycoprotein.