Received for publication June 19, 2007.
Revised July 24, 2007.
Accepted for publication July 25, 2007.

Pharmacology and antitussive efficacy of 4-(3-trifluoromethyl-pyridin-2-yl)-piperazine-1-carboxylic acid (5-trifluoromethyl-pyridin-2-yl)-amide (JNJ17203212), a TRPV1 antagonist in guinea pigs

Abstract

TRPV1 plays an integral role in modulating the cough reflex and is an attractive antitussive drug target. The purpose of this study was to characterize a TRPV1 antagonist, JNJ17203212, against the guinea pig TRPV1 receptor in-vitro followed by a proof-of-principle study in an acid-induced model of cough. The affinity of JNJ17203212 for the recombinant guinea pig TRPV1 receptor was estimated by radioligand binding and functionally characterized by antagonism of low pH and capsaicin-induced activation of the ion channel (FLIPR and electrophysiology). The nature of antagonism was further tested against the native channel in isolated guinea pig tracheal rings. Following pharmacokinetic characterization of JNJ17203212 in guinea pigs, pharmacodynamic and efficacy studies were undertaken to establish the antitussive efficacy of the TRPV1 antagonist. The pK_i of JNJ17203212 for recombinant guinea pig TRPV1 was 7.14 ± 0.06. JNJ17203212 inhibited both pH (pIC₅₀ of 7.23 ± 0.05) and capsaicin (pIC₅₀ of 6.32 ± 0.06)-induced channel activation. In whole-cell patch clamp the pIC₅₀ for inhibition of guinea pig TRPV1 was 7.3 ± 0.01. JNJ17203212 demonstrated surmountable antagonism in isolated trachea with a pK_B value of 6.2 ± 0.1. Intra-peritoneal administration of 20 mg/kg JNJ17203212 achieved a maximal plasma exposure of 8.0 ± 0.4 µM and attenuated capsaicin evoked coughs with similar efficacy to codeine (25 mg/kg). Lastly, JNJ17203212 dose dependently produced antitussive efficacy in citric-acid induced experimental cough in guinea pigs. Our data provides preclinical support for developing TRPV1 antagonists for the treatment of cough.

Key words: JNJ17203212, TRPV1, capsaicin, cough, guinea pig, resiniferatoxin