Novel oral voltage-gated sodium channel (Nav) inhibitors inhibit capsaicin induced cough in conscious guinea pigs

Abstract

Rationale: Intractable chronic cough is a serious unmet clinical problem and new therapies are needed for this condition. Na v channels are key for nerve conduction. Local anesthetics that are known to block all Na v channels are effective antitussive agents but their non-selectivity precludes their regular use in patients due to their side effects. Aim and Objectives: Our aim was to compare two novel and selective oral Na v inhibitors vs. a non-selective reference Na v inhibitor in an animal cough model. Methods: Compound potency in Na v channels was assessed using a IonWorks Quattro Automated Patch Clamp System (IC50). Cough was induced in conscious guinea pigs by exposure to aerosolized capsaicin (30µM) and cough numbers were recorded. Results: Compound A showed a dual Na v 1.7-1.8 selectivity with IC50 of 0.5 and 2.6µM, respectively, while compound B was a Na v 1.7 selective compound (IC50 0.07µM). Both compounds inhibited the capsaicin induced cough at similar levels than the pan Na v inhibitor GSK 2338345 (compound A 70%; Compound B 60%; GSK 2338345 71% at 30mg/kg p.o.). Conclusions: These two novel selective oral Na v inhibitors from two distinct chemical series are able to significantly reduce capsaicin induced cough in guinea pigs at similar levels than the non-selective reference compound GSK 2338345. Selective oral Na v inhibitors may be a valuable therapy for chronic cough with lower potential for adverse effects.