Synthesis and evaluation of (4-chlorobenzhydryl) piperazine amides as sodium channel Nav1.7 inhibitors

Blockage of voltage-gated sodium channels is used to treat neuropathic pain which is chronic and can become debilitating. Sodium channels Nav1.7-1.9 are especially attractive targets for drug discovery because of the broad therapeutic potential of their modulation. For a neuropathic pain therapy, anticonvulsant like lamotrigine, carbamazepine and a topical anesthetic such as Lidocaine are used. A growing number of clinical reports suggest that selective inhibitors of Nav1.7 are likely to be the powerful analgesics for treating a broad range of pain conditions. Therefore we evaluated 108 amide derivatives synthesized on human Nav1.7 (hNav1.7) by VIPR (voltage/ion probe reader), a fluorescence image plate reader (FLIPR) assay that used voltage-sensor fluorescence dye and stable HEK-293 cell lines expressing hNaV1.7. Ten compounds demonstrated inhibitory activity, and the two most active compounds (5 and 6) had IC₅₀ values of 8-10 μM.