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<sup>+</sup>) 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, <b>7</b> and <b>35</b>. Compounds <b>7</b> and <b>35</b> are potent inhibitors across assays and possess favorable ADMET properties. When tested in vivo, compound <b>7</b> 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.
Authors
- Ahmed Haider (ORCID: https://orcid.org/0000-0002-5204-4473)
- M Giroud
- Didier Rombach
- Philipp Schmid (ORCID: https://orcid.org/0000-0002-8286-7876)
- Sandra Steiner
- Matthias Wittwer (ORCID: https://orcid.org/0000-0003-1359-4795)
- Wolfgang Haap (ORCID: https://orcid.org/0000-0001-6845-2124)
- Sissy Kalayil (ORCID: https://orcid.org/0000-0002-6731-2055)
- Marta Mendel (ORCID: https://orcid.org/0000-0003-0202-2169)
- Emmanuel Pinard
- Uwe Grether (ORCID: https://orcid.org/0000-0002-3164-9270)
- Catherina Gasser
- Claudia Bonardi (ORCID: https://orcid.org/0000-0002-6266-3665)
- Claudio Zambaldo
- Martin Ritter (ORCID: https://orcid.org/0000-0002-2657-3187)
- Bernd Kuhn (ORCID: https://orcid.org/0000-0002-4301-562X)
- Alessandro Brigo (ORCID: https://orcid.org/0000-0001-6860-9515)
- Inken Plitzko
- Paul Westwood
- James Keaney
- Andreas Topp (ORCID: https://orcid.org/0009-0002-5511-2870)
- Manuel Hilbert (ORCID: https://orcid.org/0009-0001-2331-9685)
- Wiebke Saal (ORCID: https://orcid.org/0000-0002-6777-8664)
- Dominique Burger
- Anisha Mani
- Jörg Benz
- Paola Caramenti
- Nina Aregger
- Nora Séchet
- Matthew Bilyard
- Alexia Malnight-Alvarez
Institutions
- Roche (Switzerland) (CH)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-03-18
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c03127
- Citations
- 8
- Primary Topic
- Endoplasmic Reticulum Stress and Disease
- Type
- article
- Field-Weighted Citation Impact
- 9.21