Discovery of N′-benzyl-3-chloro-N-((1S,3R,4R)-3-((dimethylamino)methyl)-4-hydroxy-4-(3-methoxyphenyl)cyclohexyl)benzenesulfonamide as a novel selective KOR ligand,European Journal of Medicinal Chemistry

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Discovery of N′-benzyl-3-chloro-N-((1S,3R,4R)-3-((dimethylamino)methyl)-4-hydroxy-4-(3-methoxyphenyl)cyclohexyl)benzenesulfonamide as a novel selective KOR ligand
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2024-07-03 , DOI: 10.1016/j.ejmech.2024.116643
Yang Gao ₁ , Haoran Zhu ₁ , Lunan Lv ₁ , Xiaodi Xu ₁ , Wei Li ₁ , Wei Fu ₁

Affiliation

The effective management of moderate to severe pain often relies on the use of analgesic agents. However, the widespread utility of these medications is hindered by the occurrence of several undesirable side effects. In light of this challenge, there is growing interest in the development of κ opioid receptor (KOR) agonists, which have shown promise in mitigating these adverse effects. In this study, leveraging the structural scaffold of compound D (our previous study), we embarked on the design, synthesis, and evaluation of a series of N′-benzyl-3-chloro-N- ((1S,3R,4R)-3-((dimethylamino)methyl)-4-hydroxy-4-(3-methoxyphenyl)cyclohexyl)benzenesulfonamide derivatives. These compounds were subjected to comprehensive in vitro and in vivo test. Through systematic structure-activity relationship (SAR) exploration, we successfully identified compound 23p (Ki(KOR):1.9 nM) as a highly selective KOR ligand of new chemotype. 23p showed high clearance in vitro PK test, and abdominal contraction test showed potent antinociceptive effect. 23p and its O-demethyl metabolite 25 were both found in the plasma of mouse, 25 also showed potent affinity toward KOR (Ki(KOR): 3.1 nM), both they contribute to the analgesic effect. Moreover, 23p exhibited potent antinociceptive activity in abdominal constriction test, which was effectively abolished by pre-treatment of nor-BNI, a selective KOR antagonist.

中文翻译：

N′-苄基-3-氯-N-（（1S，3R，4R）-3-（（二甲氨基）甲基）-4-羟基-4-（3-甲氧基苯基）环己基）苯磺酰胺作为新型选择性KOR配体的发现

中度至重度疼痛的有效管理通常依赖于镇痛剂的使用。然而，这些药物的广泛应用受到几种不良副作用的发生阻碍。鉴于这一挑战，人们对 κ 阿片受体（KOR）激动剂的开发越来越感兴趣，这些激动剂在减轻这些不良反应方面显示出前景。在这项研究中，利用化合物 D 的结构支架（我们之前的研究），我们着手设计、合成和评估一系列 N′-苄基-3-氯-N-（（1S，3R，4R）-3-（（二甲氨基）甲基）-4-羟基-4-（3-甲氧基苯基）环己基）苯磺酰胺衍生物。这些化合物进行了全面的体外和体内测试。通过系统的构效关系（SAR）探索，我们成功鉴定化合物 23p （Ki（KOR）：1.9 nM）为新化学型的高选择性 KOR 配体。23p 体外 PK 试验显示高清除率，腹部收缩试验显示有效的镇痛作用。23p 及其 O-脱甲基代谢物 25 均存在于小鼠血浆中，25 也显示出对 KOR （Ki（KOR）： 3.1 nM）的强亲和力，它们都有助于镇痛作用。此外，23p 在腹部收缩试验中表现出有效的抗伤害活性，其被选择性 KOR 拮抗剂 nor-BNI 的预处理有效消除。

更新日期：2024-07-03

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