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

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

Abstract

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.