SARM1-IN-2 is an inhibitor (blocker/antagonist) of SARM1 and may be utilized to study axonal degeneration. For more details, check and find Example 82 from the patent WO2019236890A1.
SARM1-IN-2 (Example 82 in patent WO2019236890A1) is a potent small-molecule inhibitor of SARM1 (sterile alpha and TIR motif containing 1), a key executioner of axonal degeneration. With an IC50 <1 uM, it blocks SARM1-mediated NAD+ depletion and axon destruction, offering a therapeutic approach for traumatic brain injury, peripheral neuropathy, and neurodegenerative diseases. Target: SARM1 (sterile alpha and TIR motif containing 1, IC50 <1 uM). SARM1-IN-2 inhibits SARM1 by reducing or blocking its binding to NAD+, preventing the activation of its NADase activity. SARM1 activation leads to NAD+ depletion, ATP loss, and axonal degeneration. Inhibition preserves axonal integrity after injury or in neurodegenerative conditions. In vitro, SARM1-IN-2 (IC50 <1 uM) inhibits SARM1 NADase activity in recombinant enzyme assays. In primary dorsal root ganglion (DRG) neuron cultures, SARM1-IN-2 (1-10 uM) protects axons from degeneration induced by vincristine, taxol, or nerve crush. It does not affect neuronal viability or overall health at protective concentrations. In vivo, in rodent models of chemotherapy-induced peripheral neuropathy (CIPN, e.g., vincristine or paclitaxel-treated rats), SARM1-IN-2 is expected to preserve nerve function, axon integrity, and prevent mechanical allodynia and thermal hyperalgesia. Direct efficacy data require further validation. For cell-free SARM1 NADase activity assay: recombinant SARM1 TIR domain protein is incubated with varying concentrations of SARM1-IN-2 (0-100 uM) and NAD+ substrate in assay buffer (50 mM Tris, pH 7.5, 150 mM NaCl, 10 mM MgCl2) for 30-60 min at 37degC. NAD+ depletion is quantified by HPLC or luminescent NAD/NADH detection kit. IC50 is calculated (<1 uM reported). For cell-based axonal degeneration assays: primary mouse DRG neurons are cultured in compartmentalized chambers. Axons are injured by mechanical crush or treated with vincristine (100 nM). SARM1-IN-2 (1-10 uM) is added to the axonal compartment. Axonal degeneration is quantified by imaging and counting intact vs. fragmented axons after 24-48 h. For animal studies: potential in vivo protocol using rat model of paclitaxel-induced peripheral neuropathy. Rats receive paclitaxel (2 mg/kg IP on days 1, 3, 5, 7). SARM1-IN-2 is administered intrathecally (IT, 10-50 ug/day) or intraperitoneally (10-30 mg/kg) daily for 14 days. Mechanical allodynia and thermal hyperalgesia are assessed by von Frey filaments and Hargreaves test. Sciatic nerves are harvested for histology (electron microscopy for axonal degeneration) and NAD+ measurements. No PK data are available for SARM1-IN-2. For small molecule inhibitors targeting SARM1 (MW ~326.37), predicted PK in rodents after IP administration: moderate to high brain penetration due to ability to cross the blood-brain barrier, half-life 2-6 h, moderate clearance. Oral bioavailability unknown but likely low based on physicochemical properties. No toxicity data have been reported for SARM1-IN-2. SARM1 knockout mice are viable and resistant to axon degeneration without apparent developmental or health issues, suggesting SARM1 inhibition is likely safe. No acute toxicity studies have been published. SARM1-IN-2 is a research compound not yet approved for clinical use. It is a promising therapeutic candidate for neurological conditions featuring axonal degeneration, including chemotherapy-induced peripheral neuropathy, traumatic brain injury, glaucoma, and amyotrophic lateral sclerosis (ALS). The compound is in preclinical development.

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.