Discovery of SHR1653, a Highly Potent and Selective OTR Antagonist with Improved Blood–Brain Barrier Penetration

作者：Xin Li, Zhigao Zhang, Yang Chen, Hong Wan, Jiakang Sun, Bin Wang, Bingqiang Feng, Bing Hu, Xing-Xing Shi, Jun Feng, Lei Zhang, Feng He, Chang Bai, Lianshan Zhang, Weikang Tao · 发表于：ACS Medicinal Chemistry Letters · 年份：2019 · DOI：10.1021/acsmedchemlett.9b00186 · 被引用次数：12 · 研究领域：Neuroendocrine regulation and behavior、Neuroscience of respiration and sleep、Hypothalamic control of reproductive hormones

The oxytocin receptor (OTR) plays a major role in the control of male sexual responses. Antagonists of the OTR have been reported to inhibit ejaculation in animal models and serve as a potential treatment for premature ejaculation (PE). Herein, we describe a novel scaffold featuring an aryl substituted 3-azabicyclo [3.1.0] hexane structure. The lead compound, SHR1653, was shown to be a highly potent OTR antagonist, which exhibited excellent selectivity over V 1A R, V 1B R, and V 2 R. This novel molecule was shown to have a favorable pharmacokinetic profile across species, as well as robust in vivo efficacy in a rat uterine contraction model. Interestingly, SHR1653 exhibited excellent blood–brain barrier penetration, which might be beneficial for the treatment of CNS-related PE.