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

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.

Figure 1

Clinical compounds as OTR antagonists.

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 AUC_T 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 = (AUC_T – AUC₀)/AUC₀.

Figure 3

BBB penetration results of SHR1653 and IX-01.

Scheme 1. Synthetic Route of SHR1653