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
  • 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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