RT Journal Article
SR Electronic
T1 <em>N</em>-(2-Hydroxyethyl)-<em>N</em>,2-dimethyl-8-{[(4<em>R</em>)-5-methyl-3,4-dihydro-2<em>H</em>-chromen-4-yl]amino}imidazo[1,2-<em>a</em>]pyridine-6-carboxamide (PF-03716556), a Novel, Potent, and Selective Acid Pump Antagonist for the Treatment of Gastroesophageal Reflux Disease
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 671
OP 679
DO 10.1124/jpet.108.146415
VO 328
IS 2
A1 Hiroki Mori
A1 Hiroko Tonai-Kachi
A1 Yasuo Ochi
A1 Yasuhito Taniguchi
A1 Hiroyuki Ohshiro
A1 Nobuyuki Takahashi
A1 Takeshi Aihara
A1 Akiko Hirao
A1 Teruhisa Kato
A1 Minoru Sakakibara
A1 Yoichi Kurebayashi
YR 2009
UL http://jpet.aspetjournals.org/content/328/2/671.abstract
AB 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 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 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. The American Society for Pharmacology and Experimental Therapeutics