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.