Oxadiazolylindazole sodium channel modulators are neuroprotective toward hippocampal neurones

Abstract

We report the discovery of a new class of neuroprotective voltage-dependent sodium channel modulators exemplified by (5-(1-benzyl-1H-indazol-3-yl)-1,2,4- oxadiazol-3-yl)methanamine 11 (CFM1178). The compounds were inhibitors of [ 14C]guanidinium ion flux in rat forebrain synaptosomes and displaced binding of the sodium channel ligand [3H]BW202W92. 11 and the corresponding N2-benzyl isomer, 38 (CFM6058), demonstrated neuroprotective activity in hippocampal slices comparable to sipatrigine. CYP450 enzyme inhibition observed with 11 was reduced with 38. In electrophysiological experiments on dissociated hippocampal neurons, these two compounds caused use- and voltage-dependent block of sodium currents. Sodium channel isoform profiling against Nav1.1-1.8 demonstrated that the standard sodium channel blocker lamotrigine had modest activity against Nav1.1, while sipatrigine was generally more potent and less selective. 11 and 38 showed potent activity against Nav1.6, pointing to pharmacological block of this isoform being consistent with the neuroprotective effect. 38 also showed use dependent block of Nav1.6 in HEK cells. © 2009 American Chemical Society.