ACS medicinal chemistry letters · 2019
Discovery of SHR1653, a Highly Potent and Selective OTR Antagonist with Improved Blood-Brain Barrier Penetration.
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Li Xin, Zhang Zhigao, Chen Yang, Wan Hong, Sun Jiakang, Wang Bin, Feng Bingqiang, Hu Bing, Shi Xingxing, Feng Jun, Zhang Lei, He Feng, Bai Chang, Zhang Lianshan, Tao Weikang
Аннотация
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 V1AR, V1BR, and V2R. 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.