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发现了一种强大的SARM1基交换抑制剂,具有活体有效性

Maude Giroud¹, Bernd Kuhn¹, Sandra Steiner¹

¹Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070 Basel, Switzerland.

Journal of medicinal chemistry

|March 18, 2025

概括

研究人员发现了新的无菌alpha和TIR Motif含有1 (SARM1) 抑制剂,化合物7和35. 化合物7在外围神经损伤的小鼠模型中表现出有效性,减少神经丝光水平,为神经系统疾病提供治疗潜力.

科学领域:

神经科学是一个神经科学.
生物化学生物化学
药理学药理学是指药理学的学科.

背景情况:

无菌阿尔法和含有TIR动因1 (SARM1) 是编程轴突退化的关键酶.
轴突退化与各种神经退行性疾病有关,包括多发性硬化症和帕金森病.
准SARM1为神经系统疾病提供了潜在的治疗策略.

研究的目的:

发现和描述新型,强效和选择性SARM1抑制剂.
在临床前模型中评估已识别的SARM1抑制剂的体内疗效.

主要方法:

结构导向的药物发现方法.
在体外的酶定量测试来评估SARM1抑制.
用于药理动力学评估的ADMET分析.
在外周神经损伤的小鼠模型中的体内测试.

主要成果:

鉴定了两种新型SARM1抑制剂,即化合物7和35.
化合物7和35表现出强大的抑制和有利的ADMET特性.
化合物7在体内证明有效性,在口服后对外围神经损伤的小鼠模型中降低了血神经丝光 (NfL) 水平.

结论:

结构引导的发现产生了强大的SARM1抑制剂,具有有利的类似药物的特性.
化合物7显示为神经退行性和神经系统疾病的治疗药物有前途.
进一步开发SARM1抑制剂可能会为涉及轴突退化的疾病带来新的治疗方法.

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