Identification of CNS-Penetrant Aryl Sulfonamides as Isoform-Selective Na_V1.6 Inhibitors with Efficacy in Mouse Models of Epilepsy

Abstract

Nonselective antagonists of voltage-gated sodium (Na V ) channels have been long used for the treatment of epilepsies. The efficacy of these drugs is thought to be due to the block of sodium channels on excitatory neurons, primarily Na V 1.6 and Na V 1.2. However, these currently marketed drugs require high drug exposure and suffer from narrow therapeutic indices. Selective inhibition of Na V 1.6, while sparing Na V 1.1, is anticipated to provide a more effective and better tolerated treatment for epilepsies. In addition, block of Na V 1.2 may complement the anticonvulsant activity of Na V 1.6 inhibition. We discovered a novel series of aryl sulfonamides as CNS-penetrant, isoform-selective Na V 1.6 inhibitors, which also displayed potent block of Na V 1.2. Optimization focused on increasing selectivity over Na V 1.1, improving metabolic stability, reducing active efflux, and addressing a pregnane Xreceptor liability. We obtained compounds 30−32, which produced potent anticonvulsant activity in mouse seizure models, including a direct current maximal electroshock seizure assay.

Bidirectional Modulation of the Voltage-Gated Sodium (Nav1.6) Channel by Rationally Designed Peptidomimetics

“…In the case of the inhibitor (12), its disruption of the PPI between FGF14 and Nav1.6 could be conferred via direct binding to the FGF14 interaction site on the C-terminal tail of Nav1.6 or via binding to FGF14 and causing the protein to undergo a conformational change that makes it inaccessible to its native interaction site on the C-terminal tail of Nav1.6. Similarly, for the potentiator of FGF14:Nav1.6 complex assembly (19), its modulatory effects on the PPI could be conferred by both binding to the C-terminal tail of Nav1.6 that makes the FGF14 interaction site increasingly accessible to the regulatory protein, or, conversely, by binding to FGF14 and causing it to undergo a conformational change that affords it with increased accessibility to its interaction site on the C-terminal tail of Nav1.6. In the native system, it is expected that the protein:ligand interactions of 12 and 19 with FGF14 and the C-terminal tail of Nav1.6 will concomitantly occur and collectively enable functionally relevant modulation of FGF14:Nav1.6 complex assembly.…”

“…Heretofore, it had been shown that addition of a N-terminal benzoyl substituent (19) to tetrapeptide analogs produced an efficacious potentiator of FGF14:Nav1.6 complex assembly, whereas truncation to a tripeptide (12) yielded an inhibitor of the complex s assembly. Additionally, both 12 and 19 demonstrated promising protein:ligand binding interactions.…”

“…Given this primacy of Nav channel dysfunction in the etiology of virtually all CNS disorders, they have been the target of many drug discovery campaigns. Such efforts, however, have been of limited success, as developed lead compounds often fail to demonstrate appreciable isoform selectivity and resultantly confer undesirable off-target side effects [19].…”

Substituted N-(Pyrazin-2-yl)benzenesulfonamides; Synthesis, Anti-Infective Evaluation, Cytotoxicity, and In Silico Studies

“…Besides, chloropyrazine derivatives, specifically anilides of 6-chloropyrazine-2-carboxylic acid, were proven previously to possess in vitro antimycobacterial activity [18,19]. Generally, sulfonamides exert a wide range of biological activities, including anti-tumoral [5], anti-inflammatory [6], anti-convulsant [7], and anti-infective [8], among others. Nevertheless, several compounds containing a pyrazine core directly connected to a sulfonamide moiety-like in our case-are already documented in the literature with a wide range of pharmacological applications [9].…”

“…Generally, sulfonamides exert a wide range of biological activities, including anti-tumoral [5], anti-inflammatory [6], anti-convulsant [7], and anti-infective [8], among others. Nevertheless, Generally, sulfonamides exert a wide range of biological activities, including anti-tumoral [5], anti-inflammatory [6], anti-convulsant [7], and anti-infective [8], among others. Nevertheless, several compounds containing a pyrazine core directly connected to a sulfonamide moiety-like in our case-are already documented in the literature with a wide range of pharmacological applications [9].…”