Received for publication September 22, 2008.
Revised October 29, 2008.
Accepted for publication October 30, 2008.

PF-03716556, a novel, potent, and selective acid pump antagonist for the treatment of gastro-esophageal reflux disease

Abstract

Inhibition of H,K-ATPase is accepted as the most effective way of controlling gastric acid secretion. However, current acid suppressant therapy for gastro-esophageal reflux disease, using histamine H₂ receptor antagonists and proton pump inhibitors, does not fully meet the needs of all patients because of their mechanism of action. This study sought to characterize the in vitro and in vivo pharmacology of a novel acid pump antagonist, N-(2-Hydroxyethyl)-N,2-dimethyl-8-{[(4R)-5-methyl-3,4-dihydro-2H-chromen-4-yl]amino}imidazo[1,2-a]pyridine-6-carboxamide (PF-03716556), and to compare with other acid suppressants. Porcine, canine, and human recombinant gastric H,K-ATPase activities were measured by ion-leaky and ion-tight assay. The affinities for a range of receptors, ion channels, and enzymes were determined to analyze selectivity profile. Acid secretion in Ghosh-Schild rats and Heidenhain pouch dogs were measured by titrating perfusate and gastric juice samples. PF-03716556 demonstrated three-fold greater inhibitory activity than revaprazan, the only acid pump antagonist that has been available on the market, in ion-tight assay. The compound did not display any species differences, exhibiting highly selective profile including the canine kidney Na,K-ATPase. Kinetics experiments revealed that PF-03716556 has a competitive and reversible mode of action. More rapid onset of action than omeprazole and three-fold greater potency than revaprazan were observed in Ghosh-Schild rats and Heidenhain pouch dogs. PF-03716556, a novel acid pump antagonist, could improve upon or even replace current pharmacological treatment for GERD.

Key words: Gastro-esophageal reflux disease, Ghosh-Schild rat, H,K-ATPase, Heidenhain pouch dog, acid pump antagonist, gastric acid secretion