title: 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), a novel, potent, and selective acid pump antagonist for the treatment of gastroesophageal 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 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.
authors.affiliation: Discovery Biology Research, Nagoya Laboratories, Pfizer Global Research and Development, Pfizer Japan Inc., Taketoyo, Aichi, Japan. hiroki.mori@pfizer.com
authors.forename: Hiroki
authors.initials: H
authors.lastname: Mori
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tonai-Kachi
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Ochi
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Taniguchi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ohshiro
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Takahashi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Aihara
authors.forename: Akiko
authors.initials: A
authors.lastname: Hirao
authors.forename: Teruhisa
authors.initials: T
authors.lastname: Kato
authors.forename: Minoru
authors.initials: M
authors.lastname: Sakakibara
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Kurebayashi
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology / Q000627:therapeutic use; D001578:Benzopyrans / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005764:Gastroesophageal Reflux / Q000188:drug therapy*; D006801:Humans; D009853:Omeprazole / Q000494:pharmacology / Q000627:therapeutic use; D054328:Proton Pump Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013270:Stomach / Q000503:physiopathology; D013552:Swine
chemical_list: D000631:Aminopyridines; D000897:Anti-Ulcer Agents; D001578:Benzopyrans; D004791:Enzyme Inhibitors; C535234:N-(2-hydroxyethyl)-N,2-dimethyl-8-((5-methyl-3,4-dihydro-2H-chromen-4-yl)amino)imidazo(1,2-a)pyridine-6-carboxamide; D054328:Proton Pump Inhibitors; D009853:Omeprazole