Discovery of a Potent SARM1 Base-Exchange Inhibitor with In Vivo Efficacy

Area of Science:

• Neuroscience
• Biochemistry
• Pharmacology

Background:

• Sterile alpha and TIR Motif Containing 1 (SARM1) is a key enzyme in programmed axonal degeneration.
• Axonal degeneration is implicated in various neurodegenerative diseases, including multiple sclerosis and Parkinson's disease.
• Targeting SARM1 offers a potential therapeutic strategy for neurological disorders.

Purpose of the Study:

• To discover and characterize novel, potent, and selective SARM1 inhibitors.
• To evaluate the in vivo efficacy of identified SARM1 inhibitors in a preclinical model.

Main Methods:

• Structure-guided drug discovery approach.
• In vitro enzymatic assays to assess SARM1 inhibition.
• ADMET profiling for pharmacokinetic evaluation.
• In vivo testing in a mouse model of peripheral nerve injury.

Main Results:

• Identification of two novel SARM1 inhibitors, compounds 7 and 35.
• Compounds 7 and 35 exhibit potent inhibition and favorable ADMET properties.
• Compound 7 demonstrated in vivo efficacy, reducing plasma neurofilament light (NfL) levels in a mouse model of peripheral nerve injury after oral administration.

Conclusions:

• Structure-guided discovery yielded potent SARM1 inhibitors with favorable drug-like properties.
• Compound 7 shows promise as a therapeutic agent for neurodegenerative and neurological disorders.
• Further development of SARM1 inhibitors could lead to new treatments for conditions involving axonal degeneration.