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

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2019 Jun 22

PMID 31223461

Authors

Xin Li

Zhigao Zhang

Yang Chen

Hong Wan

Jiakang Sun

Bin Wang

Bingqiang Feng

Bing Hu

Xingxing Shi

Jun Feng

Lei Zhang

Feng He

Chang Bai

Lianshan Zhang

Weikang Tao

Affiliations

Soon will be listed here.

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 VR, VR, and VR. This novel molecule was shown to have a favorable pharmacokinetic profile across species, as well as robust 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.

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