Profile of NT-0527, a brain penetrant NLRP3 Inflammasome inhibitor suitable as an in vivo tool compound for neuroinflammatory disorders.

IF 3.6 4区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

RSC medicinal chemistry Pub Date : 2025-09-04 DOI:10.1039/d5md00639b

David Harrison, Andy Billinton, Mark G Bock, Nicholas P Clarke, Zsofia Digby, Christopher A Gabel, Nicola Lindsay, Valérie Reader, Jane Scanlon, Pamela Smolak, Peter Thornton, Heather Wescott, Alan P Watt

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Abstract

Inhibition of the NLRP3 inflammasome has emerged as a high potential treatment paradigm for the treatment of neuroinflammation, with demonstrated anti-neuroinflammatory effects in Parkinson's disease patients and a strong rationale in Alzheimer's disease and amyotrophic lateral sclerosis. To facilitate further progress in this field, brain penetrant NLRP3 inflammasome inhibitors as leads and tool compounds are required. We discovered a small molecule NLRP3 inflammasome inhibitor, NT-0527 (11), and extensively profiled this to reveal a highly potent, selective and brain penetrant compound. This was shown to be orally bioavailable, efficacious in an in vivo model of inflammation, and with good developability characteristics. However, NT-0527 exhibited CYP 2C19 time-dependent inhibition, which halted development, but this molecule could be employed as a valuable tool compound for the investigation of neuroinflammatory conditions where NLRP3 inflammasome activation is implicated.

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NT-0527是一种脑渗透NLRP3炎性体抑制剂，适合作为神经炎性疾病的体内工具化合物。

抑制NLRP3炎性小体已成为治疗神经炎症的一种极具潜力的治疗模式，在帕金森病患者中具有抗神经炎症作用，在阿尔茨海默病和肌萎缩性侧索硬化症中具有很强的理论基础。为了促进这一领域的进一步发展，需要脑渗透NLRP3炎性体抑制剂作为先导和工具化合物。我们发现了一种小分子NLRP3炎性体抑制剂NT-0527(11)，并对其进行了广泛的分析，以揭示一种高效、选择性和脑渗透的化合物。这被证明是口服生物利用，有效的体内炎症模型，并具有良好的发展性特征。然而，NT-0527表现出CYP 2C19时间依赖性抑制，这阻止了发育，但该分子可以作为一种有价值的工具化合物，用于研究涉及NLRP3炎性体激活的神经炎症状况。

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

RSC medicinal chemistry Multiple-

CiteScore

5.80

自引率

2.40%

发文量

129