Nav1.1 activator 1

Nav1.1 activator 1 (compound 4), a highly potent Nav1.1 activator with BBB penetration, increases decay time constant (tau) of Nav1.1 currents at 0.03 μM along with significant selectivity against Nav1.2, Nav1.5, and Nav1.6[1].

Signaling Pathways >> Membrane Transporter/Ion Channel >> Sodium Channel

Research Areas >> Neurological Disease

Nav1.1[1].

Nav1.1 activator 1 (compound 4) is a valuable Nav1.1 activator for further evaluation of pathophysiological functions of the Nav1.1 channel and has potential for therapeutic treatments of CNS diseases such as Dravet syndrome[1]. Animal Model: Mice[1]. Dosage: 30 mg/kg (Pharmacokinetic Analysis). Administration: IP once (Exposure was measured at 1 h after administration). Result: Intraperitoneal administration (30 mg/kg) of compound resulted in sufficient brain exposure (193 ng/g 1 h after administration), which corresponded to 13 nM of free brain concentration comparable to the in vitro potency of the compound. Had a potential use as an in vivo tool to investigate whether this type of Nav1.1 activator can restore Nav1.1 functions and modify the disease state in animal models. Could penetrate the blood-brain barrier (BBB) in humans.

[1]. Miyazaki T, et al. Discovery of novel 4-phenyl-2-(pyrrolidinyl)nicotinamide derivatives as potent Nav1.1 activators. Bioorg Med Chem Lett. 2019 Mar 15;29(6):815-820.