Обнаружение Потент SARM1 ингибатора для обмена с In Vivo Efficacy.
Обработка статьи · этапы, ошибки и управление
Ошибки и ограничения
История · было → стало
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Giroud Maude, Kuhn Bernd, Steiner Sandra, Westwood Paul, Mendel Mateusz, Mani Anisha, Pinard Emmanuel, Haap Wolfgang, Grether Uwe, Caramenti Paola, Rombach Didier, Zambaldo Claudio, Ritter Martin, Schmid Philipp, Gasser Claire, Aregger Nina, Séchet Nora, Topp Andreas, Bilyard Matthew, Malnight-Alvarez Alexia, Plitzko Inken, Hilbert Manuel, Kalayil Sissy, Burger Dominique, Bonardi Claudia, Saal Wiebke, Haider Achi, Wittwer Matthias Beat, Brigo Alessandro, Benz Jörg, Keaney James
Аннотация
Оригинал публикации
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.