Songliang Wu, Yu Sun, Yi Hu, Hongmei Zhang, Lijuan Hou, Xing Liu, Yufeng Li, Haiying He, Zhi Luo, Yuan Chen, Yuhe Wang, Weihua Shi, Liang Shen, Changqing Cao, Wei Liang, Qing Xu, Qiang Lv, Jiong Lan, Jian Li, Shuhui Chen
A series of octahydropyrrolo[3,4-c]pyrroles were synthesized and evaluated by orexin 1 and 2 receptor (OX1 & 2 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.
January 28, 2017: Bioorganic & Medicinal Chemistry Letters