发现新型取代八氢吡咯并[3,4-c]吡咯作为用于治疗失眠的双重食欲素受体拮抗剂。
Discovery of novel substituted octahydropyrrolo[3,4-c]pyrroles as dual orexin receptor antagonists for insomnia treatment.
作者信息
Wu Songliang, Sun Yu, Hu Yi, Zhang Hongmei, Hou Lijuan, Liu Xing, Li Yufeng, He Haiying, Luo Zhi, Chen Yuan, Wang Yuhe, Shi Weihua, Shen Liang, Cao Changqing, Liang Wei, Xu Qing, Lv Qiang, Lan Jiong, Li Jian, Chen Shuhui
机构信息
WuXi AppTec (Shanghai) Co. Ltd., 288 Fute Zhong Road, Shanghai 200131, China.
Yangtze River Pharmaceutical Group, Shanghai Haiyan Pharmaceutical Technology Co. Ltd., o.8, 67 Libing Road, Shanghai 201203, China.
出版信息
Bioorg Med Chem Lett. 2017 Mar 15;27(6):1458-1462. doi: 10.1016/j.bmcl.2017.01.075. Epub 2017 Jan 28.
A series of octahydropyrrolo[3,4-c]pyrroles were synthesized and evaluated by orexin 1 and 2 receptor (OX R) antagonists assays. Compound 14l with potent OXR antagonist activity and suitable pharmacokinetic behavior was chosen to be investigated in an EEG study, which demonstrated effects of sleep promotion comparable to Suvorexant. Furthermore, the di-fluro substituted analogs exhibited reduced hERG inhibition while maintaining moderate potency.
通过食欲素1和2受体（OX受体）拮抗剂试验合成并评估了一系列八氢吡咯并[3,4-c]吡咯。选择具有强效OXR拮抗剂活性和合适药代动力学行为的化合物14l进行脑电图研究，该研究表明其促睡眠作用与苏沃雷生相当。此外，二氟取代类似物在保持中等效力的同时，对人醚-去极化相关基因（hERG）的抑制作用降低。
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