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

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.

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Publication Details

Journal
ACS Medicinal Chemistry Letters
Published
2025-05-20
DOI
https://doi.org/10.1021/acsmedchemlett.5c00189
Citations
4
Primary Topic
Endoplasmic Reticulum Stress and Disease
Type
article
Field-Weighted Citation Impact
4.61
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Optimization of Brain Penetrant SARM1 Orthosteric Inhibitors and Discovery of Their Paradoxical Subinhibitory Activation

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4 citations
ACS Medicinal Chemistry Letters
Endoplasmic Reticulum Stress and Disease
4.61
article

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

Samantha A. Green, Heidi Ackerly Wallweber, Jun Liang, M. Braun, Justin Q. Ly, Bryan Chan, Jeremy M. Murray, Matthew Del Bel, Russell T. Smith, Jawahar Sudhamsu, Kwong Wah Lai, Mingshuo Zeng, Anton Delwig, Jessica M. Grandner, Rebecca Leahey, Martin S. Weber, Renwei Zhang, Xiaoli Shen, Bing‐Yan Zhu, Marika Nespi, Anjani Ganti, Flora I. Hinz, Gladys Boenig, Maria Andrea Breboneria
article en
4 citations

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.

ACS Medicinal Chemistry LettersVol. 16(6)
WuXi AppTec (China) (CN)
Zero hunger
Openalex Percentile: Top 6%
Endoplasmic Reticulum Stress and Disease
4.61
DOISourceOpenAlex
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