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Tonabersat as a Neuroprotective Compound for Amyotrophic Lateral Sclerosis
Johns Hopkins University
Small molecule
Musculoskeletal disease
Hit To Lead or Lead Optimization
• Tonabersat specifically targets and inhibits Cx43.
• Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons, and results in muscle atrophy and loss of motor control.
• Tonabersat (SB-220453) is a novel cis benzopyran derivative molecule that specifically targets and inhibits Cx43. Compared to the nonspecific gap junction inhibitors, tonabersat demonstrates better target specificity, thus minimizing the potentially undesirable effects from broad gap junction inhibition. Additionally, unlike large peptide blockers that have difficulty crossing the blood-brain barrier, tonabersat’s small size enables it to easily penetrate the blood-brain barrier to target astroglial cells in the central nervous system.
• Also, as an orally available compound, tonabersat has an excellent safety profile and is already shown to be well-tolerated in studies for patients with migraine. In vitro studies have demonstrated that tonabersat can protect motor neurons from astrocyte-induced toxicity, which may slow the process of motor neuron degeneration during ALS’s disease progression.
US20200352902A1
Cx43 hemichannels contribute to astrocyte-mediated toxicity in sporadic and familial ALS. PNAS, (2022)
