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IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2025-03-18 DOI:10.1021/acs.jmedchem.4c03127

Maude Giroud, Bernd Kuhn, Sandra Steiner, Paul Westwood, Mateusz Mendel, Anisha Mani, Emmanuel Pinard, Wolfgang Haap, Uwe Grether, Paola Caramenti, Didier Rombach, Claudio Zambaldo, Martin Ritter, Philipp Schmid, Claire Gasser, Nina Aregger, Nora Séchet, Andreas Topp, Matthew Bilyard, Alexia Malnight-Alvarez, Inken Plitzko, Manuel Hilbert, Sissy Kalayil, Dominique Burger, Claudia Bonardi, Wiebke Saal, Achi Haider, Matthias Beat Wittwer, Alessandro Brigo, Jörg Benz, James Keaney

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引用次数: 0

摘要

不育α和含 TIR 动机 1（SARM1）是一种烟酰胺腺嘌呤二核苷酸（NAD+）水解酶，在程序性轴突变性中起着核心作用。轴突变性与神经退行性疾病和神经系统疾病有关，如多发性硬化症、肌萎缩侧索硬化症、帕金森病和周围神经病。因此，开发强效和选择性 SARM1 抑制剂可能是治疗这些疾病的有效策略。我们在本文中介绍了在结构指导下发现的两种新型 SARM1 抑制剂 7 和 35。化合物 7 和 35 在各种实验中都是强效抑制剂，并具有良好的 ADMET 特性。在体内测试时，化合物 7 在小鼠周围神经损伤模型中显示出口服后的疗效，与用药物治疗的对照组小鼠相比，化合物 7 在 50 mg/kg 的剂量下可降低血浆神经丝光（NfL）水平，有望用于治疗神经退行性疾病和神经系统疾病。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Discovery of a Potent SARM1 Base-Exchange Inhibitor with In Vivo Efficacy

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Discovery of a Potent SARM1 Base-Exchange Inhibitor with In Vivo Efficacy

Sterile alpha and TIR Motif Containing 1 (SARM1) is a nicotinamide adenine dinucleotide (NAD⁺) hydrolase that plays a central role in programmed axonal degeneration. Axonal degeneration has been linked to neurodegenerative and neurological disorders such as multiple sclerosis, amyotrophic lateral sclerosis, Parkinson’s disease, and peripheral neuropathies. Therefore, developing potent and selective SARM1 inhibitors could be an effective strategy to treat these disorders. We present herein the structure-guided discovery of two novel SARM1 inhibitors, 7 and 35. Compounds 7 and 35 are potent inhibitors across assays and possess favorable ADMET properties. When tested in vivo, compound 7 showed efficacy after oral dosing in a mouse model of peripheral nerve injury by decreasing plasma neurofilament light (NfL) levels at 50 mg/kg compared with vehicle-treated control mice, holding promise for the treatment of neurodegenerative and neurological disorders.

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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.