1. Academic Validation
  2. Discovery of a Potent SARM1 Base-Exchange Inhibitor with In Vivo Efficacy

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

  • J Med Chem. 2025 Mar 27;68(6):6558-6575. doi: 10.1021/acs.jmedchem.4c03127.
Maude Giroud 1 Bernd Kuhn 1 Sandra Steiner 1 Paul Westwood 1 Mateusz Mendel 1 Anisha Mani 1 Emmanuel Pinard 1 Wolfgang Haap 1 Uwe Grether 1 Paola Caramenti 1 Didier Rombach 1 Claudio Zambaldo 1 Martin Ritter 1 Philipp Schmid 1 Claire Gasser 1 Nina Aregger 1 Nora Séchet 1 Andreas Topp 1 Matthew Bilyard 1 Alexia Malnight-Alvarez 1 Inken Plitzko 1 Manuel Hilbert 1 Sissy Kalayil 1 Dominique Burger 1 Claudia Bonardi 1 Wiebke Saal 1 Achi Haider 1 Matthias Beat Wittwer 1 Alessandro Brigo 1 Jörg Benz 1 James Keaney 1
Affiliations

Affiliation

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