Inhibition of H(+),K(+)-
ATPase is accepted as the most effective way of controlling gastric acid secretion. However, current
acid suppressant
therapy for
gastroesophageal reflux disease, using
histamine H(2) 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 it 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 3-fold greater inhibitory activity than 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine (
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 5-methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]-sulfinyl}-
benzimidazole (
omeprazole) and 3-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
gastroesophageal reflux disease.