Discovery of 2-(6-{[(1R,2R)-2-hydroxycyclohexyl]amino}-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol (ASP0965): A potent, orally active and brain-penetrable NLRP3 inflammasome inhibitor with a novel scaffold for the treatment of α-synucleinopathy.

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry Pub Date : 2025-02-01 Epub Date: 2024-12-12 DOI:10.1016/j.bmc.2024.118042

Yusuke Inagaki, Takashi Kamikubo, Ikumi Kuriwaki, Junko Watanabe, Susumu Yamaki, Maiko Iida, Kyoko Tomita, Kenichi Kakefuda, Jun Kurokawa, Tetsuo Kiso, Kengo Saba, Takanori Koike

引用次数: 0

Abstract

NLRP3 inflammasome inhibitor is a highly attractive drug target for the treatment of various inflammatory diseases. Here, we report the discovery of pyridazine derivatives as a new class of scaffold for NLRP3 inflammasome inhibitors. We optimized HTS hit 2a to improve both in vitro IL-1β inhibitory activity and the mean photo effect (MPE) value in the in vitro 3T3 neutral red uptake (NRU) phototoxicity test. As a result, we identified compound 5e (ASP0965) with brain penetrability and showing efficacy in the brain on oral administration in the rat pharmacodynamics (PD) model and the mouse α-synuclein injection model. These findings suggest that compound 5e is a promising clinical candidate for α-synucleinopathy therapeutics.

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2-（6-{[(1R,2R)-2-羟基环己基]氨基}-4,5-二甲基吡啶嗪-3-基）-5-（三氟甲基）苯酚（ASP0965）的发现：一种有效的、口服的、可穿透脑的NLRP3炎症小体抑制剂，是治疗α-突触核蛋白病的新支架。

NLRP3炎性体抑制剂是治疗多种炎性疾病的极具吸引力的药物靶点。在这里，我们报道了吡嗪衍生物作为NLRP3炎症小体抑制剂的一类新支架的发现。我们对HTS hit 2a进行优化，以提高体外3T3中性红摄取（NRU）光毒性试验中IL-1β的抑制活性和平均光效应（MPE）值。因此，我们在大鼠药效学模型和小鼠α-突触核蛋白注射模型中鉴定出化合物5e （ASP0965）具有脑穿透性，口服给药对脑有效。这些结果表明，化合物5e是α-突触核蛋白病治疗的一个有前景的临床候选药物。

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 医学-生化与分子生物学

CiteScore

6.80

自引率

2.90%

发文量

413

审稿时长

17 days

期刊介绍： Bioorganic & Medicinal Chemistry provides an international forum for the publication of full original research papers and critical reviews on molecular interactions in key biological targets such as receptors, channels, enzymes, nucleotides, lipids and saccharides. The aim of the journal is to promote a better understanding at the molecular level of life processes, and living organisms, as well as the interaction of these with chemical agents. A special feature will be that colour illustrations will be reproduced at no charge to the author, provided that the Editor agrees that colour is essential to the information content of the illustration in question.