2-Aminopyridines as Potent and Selective Nav1.8 Inhibitors Exhibiting Efficacy in a Nonhuman Primate Pain Model

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL ACS Medicinal Chemistry Letters Pub Date : 2024-05-24 DOI:10.1021/acsmedchemlett.4c00103

Michael J. Breslin*, Jeffrey W. Schubert, Deping Wang, Chienjung Huang, Michelle K. Clements, Yuxing Li, Xiaoping Zhou, Joshua D. Vardigan, Richard L. Kraus, Vincent P. Santarelli, Jason M. Uslaner, Paul J. Coleman and Shawn J. Stachel,

引用次数: 0

Abstract

Herein we describe the discovery of a 2-aminopyridine scaffold as a potent and isoform selective inhibitor of the Na_v1.8 sodium channel. Parallel library synthesis, guided by in silico predictions, rapidly transformed initial hits into a novel 2-aminopyridine lead class possessing good ADME and pharmacokinetic profiles that were able to display activity in a clinically translatable nonhuman primate capsaicin-sensitized thermode pharmacodynamic assay. Progress toward the lead identification, optimization, and in vivo efficacy of these compounds will be discussed.

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作为强效选择性 Nav1.8 抑制剂的 2-氨基吡啶在非人灵长类疼痛模型中展现疗效

在此，我们介绍了 2-氨基吡啶支架作为 Nav1.8 钠通道强效同种异构选择性抑制剂的发现。在硅学预测的指导下，平行文库合成迅速将最初的命中物转化为新型 2-氨基吡啶先导类药物，该类药物具有良好的 ADME 和药代动力学特征，能够在可临床转化的非人灵长类动物辣椒素致敏热效药效学试验中显示出活性。我们将讨论这些化合物在先导化合物鉴定、优化和体内药效方面的进展。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.