Selective NaV1.7 Antagonists with Long Residence Time Show Improved Efficacy against Inflammatory and Neuropathic Pain

Abstract

Selective block of Na1.7 promises to produce non-narcotic analgesic activity without motor or cognitive impairment. Several Na1.7-selective blockers have been reported, but efficacy in animal pain models required high multiples of the IC for channel block. Here, we report a target engagement assay using transgenic mice that has enabled the development of a second generation of selective Nav1.7 inhibitors that show robust analgesic activity in inflammatory and neuropathic pain models at low multiples of the IC. Like earlier arylsulfonamides, these newer acylsulfonamides target a binding site on the surface of voltage sensor domain 4 to achieve high selectivity among sodium channel isoforms and steeply state-dependent block. The improved efficacy correlates with very slow dissociation from the target channel. Chronic dosing increases compound potency about 10-fold, possibly due to reversal of sensitization arising during chronic injury, and provides efficacy that persists long after the compound has cleared from plasma.

Structural basis of α-scorpion toxin action on Na v channels

“…1B and 5E, fig. S6, and Movie 1) (50)(51)(52)54). AaH2 embraces a highly conserved PM glycan on the VSD4-Na v PaS channel ( Fig.…”

Fluorescence Imaging of Peripheral Nerves by a Nav1.7-Targeted Inhibitor Cystine Knot Peptide

“…Third, it is unclear to what degree Na v 1.7 must be inhibited, or what population of Na v 1.7 channels must be inhibited, to induce an analgesic effect. 24,37 Lastly, it remains to be seen if a lifelong absence and the temporary deactivation of Na v 1.7 result in comparable phenotypes. 38 For an imaging agent, some of the above-mentioned translational hurdles do not apply, because imaging agents should not elicit a pharmacological response.…”

Antibodies and venom peptides: new modalities for ion channels

“…1B), recently failed in patients suffering from painful diabetic neuropathy 34 , which led Pfizer to stop further development activities. Bankar et al suggested this failure possibly reflected insufficient Na V 1.7 targeting in the clinical study and recommend the evaluation of acyl-sulfonamides with better physiochemical and pharmacological properties 35 , including a longer residence time on the target 36 . Since PF-05089771 is intentionally peripherally restricted, compounds with improved blood brain barrier (BBB) penetrability in humans, might better engage NaV1.7 channels expressed close to or on the bouton of dorsal root ganglion (DRG) neuron dorsal horn synapse.…”