Document Detail

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.
MedLine Citation:
PMID:  20624992     Owner:  NLM     Status:  MEDLINE    
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.
Yasunobu Hori; Akio Imanishi; Jun Matsukawa; Yasuhiro Tsukimi; Haruyuki Nishida; Yasuyoshi Arikawa; Keizo Hirase; Masahiro Kajino; Nobuhiro Inatomi
Publication Detail:
Type:  In Vitro; Journal Article     Date:  2010-07-12
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  335     ISSN:  1521-0103     ISO Abbreviation:  J. Pharmacol. Exp. Ther.     Publication Date:  2010 Oct 
Date Detail:
Created Date:  2010-09-21     Completed Date:  2010-10-21     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  231-8     Citation Subset:  IM    
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Osaka, Japan.
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MeSH Terms
2-Pyridinylmethylsulfinylbenzimidazoles / pharmacology
Dithiothreitol / pharmacology
Gastric Acid / secretion
Gastric Mucosa / drug effects,  enzymology,  metabolism
H(+)-K(+)-Exchanging ATPase / antagonists & inhibitors
Histamine / pharmacology
Hydrogen-Ion Concentration
Imidazoles / pharmacology
Potassium / metabolism*
Proton Pump Inhibitors / pharmacology*
Pyrroles / pharmacology*
Rats, Sprague-Dawley
Stomach / chemistry
Sulfonamides / pharmacology*
Reg. No./Substance:
0/1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine; 0/2-Pyridinylmethylsulfinylbenzimidazoles; 0/Imidazoles; 0/Proton Pump Inhibitors; 0/Pyrroles; 0/Sulfonamides; 103577-45-3/lansoprazole; 3483-12-3/Dithiothreitol; 51-45-6/Histamine; 7440-09-7/Potassium; 76081-98-6/Sch 28080; EC ATPase

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