Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 May 29;10(6):996-1001.
doi: 10.1021/acsmedchemlett.9b00186. eCollection 2019 Jun 13.

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

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

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

Xin Li et al. ACS Med Chem Lett. .

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.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Clinical compounds as OTR antagonists.
Figure 2
Figure 2
In vivo efficacy of IX-01 and SHR1653 in an anesthetized rat uterine contraction model. *p < 0.05, vs vehicle, one-way ANOVA, Dunnett’s posthoc test; n = 10, except vehicle, n = 17. The contractile response was calculated by the ratio of AUC changes in the intraluminal uterine pressure to the baseline AUC0. The baseline AUC0 was the 5 min area under the curve pressure prior to oxytocin dosing. The AUCT was the 5 min area under the curve pressure after oxytocin dosing. The changes in the baseline AUC ratio (δAUC ratio) were calculated δAUC ratio = (AUCT – AUC0)/AUC0.
Figure 3
Figure 3
BBB penetration results of SHR1653 and IX-01.
Scheme 1
Scheme 1. Synthetic Route of SHR1653
See this image and copyright information in PMC

References

    1. Gimpl G.; Fahrenholz F. The oxytocin receptor system: structure, function, and regulation. Physiol. Rev. 2001, 81, 629–683. 10.1152/physrev.2001.81.2.629. - DOI - PubMed
    1. Zingg H. H.; Laporte S. A. The oxytocin receptor. Trends Endocrinol. Metab. 2003, 14, 222–227. 10.1016/S1043-2760(03)00080-8. - DOI - PubMed
    1. Gullam J. E.; Chatterjee J.; Thornton S. Preterm labor: novel treatments. Drug Discovery Today: Ther. Strategies 2005, 2, 47–52. 10.1016/j.ddstr.2005.05.023. - DOI
    1. Lamont R. F.; Kam K. Y. R. Atosiban as a tocolytic for the treatment of spontaneous preterm labor. Expert Rev. Obstet. Gynecol. 2008, 3, 163–174. 10.1586/17474108.3.2.163. - DOI
    1. Moraloglu O.; Tonguc E.; Var T.; Zeyrek T.; Batioglu S. Treatment with oxytocin antagonists before embryo transfer may increase implantation rates after IVF. Reprod. BioMed. Online 2010, 21, 338–343. 10.1016/j.rbmo.2010.04.009. - DOI - PubMed