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

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.
Xin Li 1,  Zhigao Zhang 1,  Yang Chen 1,  Hong Wan 1,  Jiakang Sun 1,  Bin Wang 1,  Bingqiang Feng 1,  Bing Hu 1,  Xingxing Shi 1,  Jun Feng 1,  Lei Zhang 1,  Feng He 1 2,  Chang Bai 1,  Lianshan Zhang 3,  Weikang Tao 1 2
Affiliations

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.
PMID: 31223461 DOI: 10.1021/acsmedchemlett.9b00186
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 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.

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