Preclinical Pharmacokinetic and Pharmacological Profiling of B339, a Novel SARM1 Inhibitor for the Treatment of Vincristine-induced Peripheral Neuropathy.

PURPOSE: Despite the extensive knowledge about the role of Sterile α and TIR motif-containing protein-1 (SARM1) inhibition in the prevention of axonal degeneration, very few pharmacological inhibitors of SARM1 have been discovered and tested in preclinical models, with limited knowledge about their pharmacokinetic properties. METHODS: In this study, a thioamide small-molecule library was screened against SARM1 via structure-guided molecular docking and the inhibitory activity of the resulting hits was further evaluated using High Performance Liquid Chromatography (HPLC) based in vitro NADase assay. In vitro drug metabolism and in vivo pharmacokinetic studies were performed for the best candidate, and the compound was tested in a preclinical mouse model of vincristine-induced peripheral neuropathy (VIPN). RESULTS: A benzothioamide derivative, B339, emerged as a potent SARM1 inhibitor (IC50 7.215 μM) through our in silico and in vitro screening. The compound exhibited absolute bioavailability of 53% when administered through intraperitoneal (IP) route but appear to have rapid clearance. In a mouse model of VIPN, B339 (30 mg/kg IP) demonstrated prevention of thermal and mechanical allodynia, and motor impairment, improved sensory and motor nerve conduction, and prevented axonal degeneration. CONCLUSIONS: The study provided discovery and in-depth pharmacokinetic characterization of a novel SARM1 inhibitor, B339, and demonstrated its pharmacological potential for the treatment of VIPN.