Discovery of SHR1653, a Highly Potent and Selective OTR Antagonist with Improved Blood-Brain Barrier Penetration.,ACS Medicinal Chemistry Letters

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Discovery of SHR1653, a Highly Potent and Selective OTR Antagonist with Improved Blood-Brain Barrier Penetration.
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2019-05-29 00:00:00 , 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}

Affiliation

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.

中文翻译：

发现了SHR1653，这是一种具有增强的血脑屏障渗透性的强效选择性OTR拮抗剂。

催产素受体（OTR）在控制男性性反应中起主要作用。据报道，在动物模型中，OTR的拮抗剂可抑制射精，并可作为早泄（PE）的潜在治疗方法。在这里，我们描述了一种新型的脚手架，其特征是芳基取代的3-氮杂双环[3.1.0]己烷结构。铅化合物SHR1653被证明是一种高效的OTR拮抗剂，相对于V _1A R，V _1B R和V ₂ R表现出优异的选择性。该新型分子也显示出对整个物种都具有良好的药代动力学特征体内一样健壮在大鼠子宫收缩模型中的功效。有趣的是，SHR1653表现出出色的血脑屏障穿透性，可能对中枢神经系统相关PE的治疗有益。

更新日期：2019-05-29

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