Engineering a Potent, Long-Acting, and Periphery-Restricted Oxytocin Receptor Agonist with Anorexigenic and Body Weight Reducing Effects.,Journal of Medicinal Chemistry

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Engineering a Potent, Long-Acting, and Periphery-Restricted Oxytocin Receptor Agonist with Anorexigenic and Body Weight Reducing Effects.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2019-12-18 , DOI: 10.1021/acs.jmedchem.9b01862
Elsa Pflimlin ₁ , Zhihong Zhou ₁ , Zaid Amso ₁ , Qiangwei Fu ₁ , Candy Lee ₁ , Avinash Muppiddi ₁ , Sean B Joseph ₁ , Vân Nguyen-Tran ₁ , Weijun Shen ₁

Affiliation

The effects of oxytocin on food intake and body weight reduction have been demonstrated in both animal models and human clinical studies. Despite being efficacious, oxytocin is enzymatically unstable and thus considered to be unsuitable for long-term use in patients with obesity. Herein, a series of oxytocin derivatives were engineered through conjugation with fatty acid moieties that are known to exhibit high binding affinities to serum albumin. One analog (OT-12) in particular was shown to be a potent full agonist at the oxytocin receptor (OTR) in vitro with good selectivity and long half-life (24 h) in mice. Furthermore, OT-12 is peripherally restricted, with very limited brain exposure (1/190 of the plasma level). In a diet-induced obesity mouse model, daily subcutaneous administration of OT-12 exhibited more potent anorexigenic and body weight reducing effects than carbetocin. Thus, our results suggest that the long-acting, peripherally restricted OTR agonist may offer potential therapeutic benefits for obesity.

中文翻译：

设计一种有效，长效且受周围环境限制的催产素受体激动剂，具有减轻厌食症和减轻体重的作用。

催产素对食物摄入和减轻体重的作用已在动物模型和人体临床研究中得到证实。尽管有效，催产素在酶学上是不稳定的，因此被认为不适用于肥胖症患者的长期使用。本文中，通过与已知对血清白蛋白表现出高结合亲和力的脂肪酸部分缀合来设计一系列催产素衍生物。特别是一种类似物（OT-12）被证明是体外催产素受体（OTR）的有效全效激动剂，在小鼠中具有良好的选择性和长的半衰期（24小时）。此外，OT-12受外围限制，大脑的暴露量非常有限（血浆水平的1/190）。在饮食诱发的肥胖小鼠模型中，每天皮下给予OT-12的效果比羧甲霉素要强。因此，我们的结果表明，长效，外周限制性的OTR激动剂可能为肥胖症提供潜在的治疗益处。

更新日期：2019-12-19

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