title: Antisecretory and antiulcer activities of a novel proton pump inhibitor AG-1749 in dogs and rats.
abstract: The antisecretory and antiulcer activities of 2[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl] sulfinyl]-1H-benzimidazole (AG-1749) were investigated in dogs and rats. AG-1749 inhibited both the (H+ + K+)-adenosine triphosphatase activity in canine gastric microsomes and dibutyryl cyclic AMP-stimulated acid formation in isolated canine parietal cells and suppressed the acid secretion stimulated by histamine, pentagastrin, bethanechol or a peptone meal in Heidenhain pouch dogs; the ID50 values were between 0.2 and 0.7 mg/kg p.o. AG-1749 inhibited both the histamine-stimulated and the basal acid secretion in pylorusligated rats and prevented water immersion stress or aspirin-induced gastric lesions and mepirizole or cysteamine-induced duodenal ulcers in rats; the ID50 values were between 0.3 to 3.6 mg/kg p.o. or i.d. Furthermore, AG-1749 prevented gastric lesions induced by absolute ethanol or acidified aspirin, and accelerated the healing of acetic acid-induced gastric or duodenal ulcers in rats. The inhibitory potency of AG-1749 in dogs was much the same as that of omeprazole and about half that of ranitidine. However, it was about 2 to 10 times more potent than omeprazole and 4 to 34 times more potent than ranitidine in rats. These results suggest that AG-1749 exerts prominent antiulcer activities mainly by suppressing acid secretion via an inhibition of a proton pump in gastric parietal cells and partly by protecting the gastrointestinal mucosa against various ulcerative stimuli.
authors.affiliation: Central Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Satoh
authors.forename: N
authors.initials: N
authors.lastname: Inatomi
authors.forename: H
authors.initials: H
authors.lastname: Nagaya
authors.forename: I
authors.initials: I
authors.lastname: Inada
authors.forename: A
authors.initials: A
authors.lastname: Nohara
authors.forename: N
authors.initials: N
authors.lastname: Nakamura
authors.forename: Y
authors.initials: Y
authors.lastname: Maki
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors*; D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D004285:Dogs; D005744:Gastric Acid / Q000378:metabolism*; D005753:Gastric Mucosa / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D005755:Gastrins / Q000097:blood; D017506:H(+)-K(+)-Exchanging ATPase; D066298:In Vitro Techniques; D064747:Lansoprazole; D008297:Male; D009853:Omeprazole / Q000031:analogs & derivatives* / Q000494:pharmacology; D010434:Pepsin A / Q000378:metabolism; D010437:Peptic Ulcer / Q000188:drug therapy; D011522:Protons; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000897:Anti-Ulcer Agents; D005755:Gastrins; D011522:Protons; D064747:Lansoprazole; D010434:Pepsin A; D000251:Adenosine Triphosphatases; D017506:H(+)-K(+)-Exchanging ATPase; D009853:Omeprazole