title: 1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate (TAK-438), a novel and potent potassium-competitive acid blocker for the treatment of acid-related diseases.
abstract: Proton pump inhibitors (PPIs) are widely used in the treatment of acid-related diseases. However, several unmet medical needs, such as suppression of night-time acid secretion and rapid symptom relief, remain. In this study, we investigated the pharmacological effects of 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate (TAK-438), a novel potassium-competitive acid blocker (P-CAB), on gastric acid secretion in comparison with lansoprazole, a typical PPI, and SCH28080 [3-(cyanomethyl)-2-methyl,8-(phenylmethoxy)imidazo(1,2-a)pyridine], a prototype of P-CAB. TAK-438, SCH28080, and lansoprazole inhibited H(+),K(+)-ATPase activity in porcine gastric microsomes with IC(50) values of 0.019, 0.14, and 7.6 μM, respectively, at pH 6.5. The inhibitory activity of TAK-438 was unaffected by ambient pH, whereas the inhibitory activities of SCH28080 and lansoprazole were weaker at pH 7.5. The inhibition by TAK-438 and SCH28080 was reversible and achieved in a K(+)-competitive manner, quite different from that by lansoprazole. TAK-438, at a dose of 4 mg/kg (as the free base) orally, completely inhibited basal and 2-deoxy-d-glucose-stimulated gastric acid secretion in rats, and its effect on both was stronger than that of lansoprazole. TAK-438 increased the pH of gastric perfusate to a higher value than did lansoprazole or SCH28080, and the effect of TAK-438 was sustained longer than that of lansoprazole or SCH28080. These results indicate that TAK-438 exerts a more potent and longer-lasting inhibitory action on gastric acid secretion than either lansoprazole or SCH28080. TAK-438 is a novel antisecretory drug that may provide a new option for the patients with acid-related disease that is refractory to, or inadequately controlled by, treatment with PPIs.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Osaka, Japan.
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Hori
authors.forename: Akio
authors.initials: A
authors.lastname: Imanishi
authors.forename: Jun
authors.initials: J
authors.lastname: Matsukawa
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Tsukimi
authors.forename: Haruyuki
authors.initials: H
authors.lastname: Nishida
authors.forename: Yasuyoshi
authors.initials: Y
authors.lastname: Arikawa
authors.forename: Keizo
authors.initials: K
authors.lastname: Hirase
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kajino
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Inatomi
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000494:pharmacology; D000818:Animals; D004229:Dithiothreitol / Q000494:pharmacology; D005744:Gastric Acid / Q000378:metabolism; D005753:Gastric Mucosa / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006632:Histamine / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D007700:Kinetics; D064747:Lansoprazole; D008026:Ligation; D008297:Male; D011188:Potassium / Q000378:metabolism*; D054328:Proton Pump Inhibitors / Q000494:pharmacology*; D011708:Pylorus; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013270:Stomach / Q000737:chemistry; D013449:Sulfonamides / Q000494:pharmacology*; D013552:Swine
chemical_list: C552956:1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine; D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D007093:Imidazoles; D054328:Proton Pump Inhibitors; D011758:Pyrroles; D013449:Sulfonamides; C035235:Sch 28080; D064747:Lansoprazole; D006632:Histamine; D011188:Potassium; D004229:Dithiothreitol