ICA-121431 [2,2-diphenyl-N-(4-(N-thiazol-2-ylsulfamoyl)phenyl) acetamide, a small molecule inhibitor, targets the extracellular amino acids in S2 and S3 in VSDIV (domain IV voltage sensor), which is essential for Hm1a efficacy. In humans, ICA-121431 blocks TTX-sensitive Nav1.3 sodium channels upregulated in HEK-293 cells.
ICA-121431 is a potent, selective inhibitor of the human Nav1.3 and Nav1.1 voltage gated sodium channels (IC50 = 19 nM) with little or no activity against human Nav1.5 or Nav1.7 channels.