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

ABSTRACT: 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_1AR, V_1BR, 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.

SUBMITTER: Li X

PROVIDER: S-EPMC6580551 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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

Li Xin X Zhang Zhigao Z Chen Yang Y Wan Hong H Sun Jiakang J Wang Bin B Feng Bingqiang B Hu Bing B Shi Xingxing X Feng Jun J Zhang Lei L He Feng F Bai Chang C Zhang Lianshan L Tao Weikang W

ACS medicinal chemistry letters 20190529 6

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<sub>1A</sub>R, V<sub>1B</sub>R, and ...[more]

PMID: 31223461

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