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

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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 ′-benzyl-3-chloro-- ((,,)-3-((dimethylamino)methyl)-4-hydroxy-4-(3-methoxyphenyl)cyclohexyl)benzenesulfonamide derivatives. These compounds were subjected to comprehensive and test. Through systematic structure-activity relationship (SAR) exploration, we successfully identified compound (:1.9 nM) as a highly selective KOR ligand of new chemotype. showed high clearance PK test, and abdominal contraction test showed potent antinociceptive effect. and its -demethyl metabolite were both found in the plasma of mouse, also showed potent affinity toward KOR ((KOR): 3.1 nM), both they contribute to the analgesic effect. Moreover, 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：

发现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

中度至重度疼痛的有效治疗通常依赖于镇痛剂的使用。然而，这些药物的广泛使用受到一些不良副作用的发生的阻碍。鉴于这一挑战，人们对开发 κ 阿片受体 (KOR) 激动剂越来越感兴趣，该激动剂在减轻这些不良反应方面显示出希望。在本研究中，利用化合物D（我们之前的研究）的结构支架，我们开始设计、合成和评估一系列'-benzyl-3-chloro-- ((,,)-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。对这些化合物进行了综合和测试。通过系统的构效关系 (SAR) 探索，我们成功鉴定出化合物 (:1.9 nM) 作为新化学型的高选择性 KOR 配体。 PK试验显示高清除率，腹部收缩试验显示有效的镇痛作用。及其β-去甲基代谢物均在小鼠血浆中发现，也对 KOR ((KOR): 3.1 nM) 表现出强大的亲和力，两者均有助于镇痛作用。此外，在腹部收缩试验中表现出有效的抗伤害活性，通过选择性 KOR 拮抗剂 Nor-BNI 的预处理可有效消除该活性。

更新日期：2024-07-03

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