Development and characterization of pyridyl carboxamides as potent and highly selective Nav1.8 inhibitors

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-12-05 DOI:10.1016/j.bmcl.2024.130059

Michael Poslusney , Glen Ernst , Yifang Huang , Aaron C. Gerlach , Mark L. Chapman , Sónia Santos , James C. Barrow

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引用次数: 0

Abstract

The voltage-gated sodium channel Na_v1.8 (SCN10A) has strong genetic and pharmacological validation as a potential target for treating acute and chronic pain. While several different chemotypes have been advanced as selective inhibitors, a quinoxaline carboxamide core structure was identified as a particularly attractive core structure due to very high sodium channel subtype selectivity. However, poor solubility and overall ADME properties need to be improved. Scaffold hopping to a central trifluoromethyl pyridine followed by optimization of distal substituents resulted in improved overall properties. Several advanced lead compounds have been identified with excellent potency, selectivity, solubility, and pharmacokinetics. Preliminary mechanism of action studies suggest that this class of compounds are voltage and state independent inhibitors that bind to a novel site on the Na_v1.8 channel.

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吡啶基羧酰胺作为高效、高选择性Nav1.8抑制剂的开发与表征。

电压门控钠通道Nav1.8 （SCN10A）作为治疗急性和慢性疼痛的潜在靶点具有很强的遗传学和药理学验证。虽然几种不同的化学型已经作为选择性抑制剂被提出，但由于具有非常高的钠通道亚型选择性，喹诺啉羧酰胺核心结构被确定为特别有吸引力的核心结构。然而，ADME的溶解度差和整体性能有待改善。支架跳跃到中心三氟甲基吡啶，然后优化远端取代基，从而改善了整体性能。一些先进的先导化合物已被确定具有良好的效力，选择性，溶解度和药代动力学。初步的作用机制研究表明，这类化合物是电压和状态无关的抑制剂，可结合Nav1.8通道上的新位点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Bioorganic & Medicinal Chemistry Letters 医学-医药化学

CiteScore

5.70

自引率

3.70%

发文量

463

审稿时长

27 days

期刊介绍： Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.