This letter describes the structure-activity relationship studies of a voltage-gated sodium channel (VGSC) blocker SV188 guided by its docking model in the lacosamide binding site of Na<inf>V</inf>1.7. Seventeen analogs of SV188 were designed, synthesized, and evaluated for whole cell I<inf>Na</inf> blockade and cytotoxicity using metastatic medullary thyroid cancer cell line MZ-CRC-1. Three analogs exhibited improved I<inf>Na</inf> blockade compared to SV188. Thirteen analogs showed reduced cytotoxicity compared to SV188. Three selected compounds were further evaluated for their cell invasion inhibition activities. All three compounds displayed cell invasion inhibitory activities that were better than those of SV188. The most promising lead compound IIB7 showed no cytotoxicity to MZ-CRC-1 cells up to 100 μM and inhibited VGSC-mediated cell invasion by 71% at 15 μM.