SARM1 (Sterile alpha and TIR Motif Containing 1) is the central executioner of axonal decay and plays a pivotal role in the pathogenesis of various neuropathies and neurodegenerative diseases. Stress-induced activation of SARM1 triggers rapid NAD⁺ depletion, resulting in energetic failure and the physical breakdown of axons. Consequently, SARM1 has emerged as a high-priority target for small-molecule neuroprotective therapies.[1,2] Herein, we report the structure-based optimization of a known ligand class,[3] supported by quantum-mechanical (QM) calculations, which led to the discovery of two potent lead compounds, 1 and 2.[4]
While both compounds demonstrated potent SARM1 inhibition in biochemical and cellular assays, high selectivity against related NADases, and robust protection of iPSC-derived motor neurons from chemically induced degeneration, compound 1 was prioritized for further development due to its superior ADMET profile.
In a spared nerve injury (SNI) mouse model of neuropathy, oral administration of compound 1 (50 mg/kg) significantly reduced plasma neurofilament light (NfL)—a clinical biomarker of axonal injury—confirming robust target engagement and in vivo efficacy. Interestingly, a lower dose (2 mg/kg) paradoxically increased NfL levels, suggesting a complex, dose-dependent pharmacology. These findings validate our rational design approach and provide critical insights into the development of base-exchange inhibitors for treating neurological disorders characterized by axonal degeneration.

[1] J. M. Osterloh, J. Yang, T. M. Rooney, A. N. Fox, R. Adalbert, E. H. Powell, A. E. Sheehan, M. A. Avery, R. Hackett, M. A. Logan, J. M. MacDonald, J. S. Ziegenfuss, S. Milde, Y.-J. Hou, C. Nathan, A. Ding, R. H. Brown, Jr., L. Conforti, M. Coleman, M. Tessier-Lavigne, S. Züchner, and M. R. Freeman, Science, 2012, 337, 481-484

[2] H. S. Loring, P. R. Thompson, Cell Chemical Biology, 2020, 27, 1-13

[3] M. Bratkowski, T. C. Burdett, J. Danao, X. Wang, P. Mathur, W. Gu, J. A. Beckstead, S. Talreja, Y.-S. Yang, G. Danko, J. H. Park, M. Walton, S. P. Brown, C. M. Tegley, P. R. B. Joseph, C. H. Reynolds, S. Sambashivan, Neuron, 2022, 110, 3711-3726

[4] M. Giroud, B. Kuhn, S. Steiner, P. Westwood, M. Mendel, A. Mani, E. Pinard, W. Haap, U. Grether, P. Caramenti, D. Rombach, C. Zambaldo, M. Ritter, P. Schmid, C. Gasser, N. Aregger, N. Séchet, A. Topp, M. Bilyard, A. Malnight-Alvarez, I. Plitzko, M. Hilbert, S. Kalayil, D. Burger, C. Bonardi, W. Saal, A. Haider, M. B. Wittwer, A. Brigo, J. Benz, James Keaney, Journal of Medicinal Chemistry, 2025, 68, 6558-6575