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. 2025 May 20;16(6):1147-1154.
doi: 10.1021/acsmedchemlett.5c00189. eCollection 2025 Jun 12.

Optimization of Brain Penetrant SARM1 Orthosteric Inhibitors and Discovery of Their Paradoxical Subinhibitory Activation

Samantha A Green  1 , Russell T Smith  1 , Jessica M Grandner  1 , Mingshuo Zeng  1 , Matthew Del Bel  1 , Bing-Yan Zhu  1 , Jun Liang  1 , Marie-Gabrielle Braun  1 , Jawahar Sudhamsu  1 , Heidi Ackerly Wallweber  1 , Gladys Boenig  1 , Jeremy Murray  1 , Xiaoli Shen  2 , Renwei Zhang  2 , Kwong Wah Lai  2 , Anton Delwig  1 , Maria Andrea Breboneria  1 , Justin Ly  1 , Anjani Ganti  1 , Marika Nespi  1 , Martin Weber  1 , Rebecca Leahey  1 , Flora I Hinz  1 , Bryan K Chan  1
Affiliations

Optimization of Brain Penetrant SARM1 Orthosteric Inhibitors and Discovery of Their Paradoxical Subinhibitory Activation

Samantha A Green et al. ACS Med Chem Lett. .

Abstract

SARM1 (sterile alpha and Toll/interleukin-1 receptor motif-containing 1) has recently emerged as a promising therapeutic target for several neurodegenerative diseases. Herein, we detail our optimization of SARM1 orthosteric base exchange inhibitors. Early chemical matter was found to be substrates for either Pgp/MDR1 or breast cancer resistant protein (BCRP), resulting in compounds with poor overall brain exposure in rodents. Using structure-based drug design, we identified the crucial interactions for driving adduct formation and subsequently optimized the molecules to eliminate the MDR1 and BCRP efflux, yielding tool compounds with sufficient brain penetration to have a pharmacodynamic (PD) effect. Ultimately, we found these compounds activated SARM1 at low doses, leading to serious adverse events in vivo. These preclinical findings highlight the liability for these base exchange inhibitors for further progression.

Keywords: NAD hydrolase; SARM1; neurodegeneration; paradoxical activation; structure-based design.

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