Pharmacological profile of a novel, potent and oral TRPA1 antagonist. Characterization in a preclinical model of induced cough

Abstract

Introduction: Treatment of chronic cough is an unmet medical need impairing patients9 quality of life. Transient Receptor Potential Ankyrin 1 (TRPA1) channels may provide a safe opportunity to target cough response at the periphery of the cough reflex arc. Poor potency and physicochemical properties of available TRPA1 antagonists are hampering their advance in the clinics. Here we describe a novel, potent and orally available TRPA1 antagonist, compound A, and its profile in preclinical models of cough. Objectives To profile the TRPA1 antagonist Compound A in in vitro assays and in a preclinical model of induced cough. In vitro profile was compared with that of HC030031. Methods: Potency of the compounds was assessed in calcium fluorescence based assays and electrophysiology in cells overexpressing TRPA1. Inhibition of isolated guinea pig (gp) vagus nerve depolarization induced by acrolein was used as functional in vitro assay. Cough was induced upon nebulization of 10mM Allyl Isothiocyanate (AITC) for 10 minutes in conscious gp individually placed into whole body plethysmography chambers (Buxco). Results: Compound A showed a potent TRPA1 antagonist activity with enhanced efficacy at inhibiting isolated gp vagus nerve depolarization (EC50=80nM). Favorable oral pharmacokinetic profile translated in a relevant efficacy at inhibiting cough induced by AITC in gp (ED50=0.17mg/kg). Conclusions: Compound A is an orally available, potent and novel TRPA1 antagonist that has proven to be efficacious in a mechanistic model of induced cough. Promising profile of Compound A suggests it could be useful for the treatment of chronic cough associated to respiratory diseases.