Synthesis and Pharmacological Evaluation of 3-Amino-1-(5-indanyloxy)-2-propanol Derivatives as Potent Sodium Channel Blockers for the Treatment of Stroke

In investigating potent sodium (Na+) channel blockers for the treatment of ischemic stroke, we synthesized a novel series of 3-amino-1-(5-indanyloxy)-2-propanol derivatives and evaluated their inhibitory effects on neuronal Na+ channels. The 3-amino-1-(5-indanyloxy)-2-propanol derivatives exhibited potent blocking activity for Na+ channels and a significantly low affinity for dopamine D2 receptors, which demonstrates a minimal clinical risk for extrapyramidal side effects. In particular, compound 4b, a 3-amino-1-(5-indanyloxy)-2-propanol derivative bearing a benzimidazole moiety, showed desirable neuroprotective activity in a rat transient middle cerebral artery occlusion model. Furthermore, compound 4b displayed a high binding affinity for neurotoxin receptor site 2 of the Na+ channels, which suggests that 4b would act as a use-dependent Na+ channel blocker in sustained depolarization during ischemic stroke.