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

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

doi:10.1021/acsmedchemlett.9b00186

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

ACS Med Chem Lett. 2019 May 29;10(6):996-1001. doi: 10.1021/acsmedchemlett.9b00186. eCollection 2019 Jun 13.

Authors

Xin Li¹, Zhigao Zhang¹, Yang Chen¹, Hong Wan¹, Jiakang Sun¹, Bin Wang¹, Bingqiang Feng¹, Bing Hu¹, Xingxing Shi¹, Jun Feng¹, Lei Zhang¹, Feng He^{1

2}, Chang Bai¹, Lianshan Zhang³, Weikang Tao^{1

2}

Affiliations

¹ Shanghai Hengrui Pharmaceutical CO., LTD., 279 Wenjing Road, Shanghai 200245, China.
² Chengdu Suncadia Medicine Co., LTD., 88 South Keyuan Road, Chengdu, Si Chuan 610000, China.
³ Jiangsu Hengrui Medicine CO., LTD., Lianyungang, Jiangsu 222047, China.

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.