| 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. | |
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MedLine Citation:
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PMID: 20624992 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Yasunobu Hori; Akio Imanishi; Jun Matsukawa; Yasuhiro Tsukimi; Haruyuki Nishida; Yasuyoshi Arikawa; Keizo Hirase; Masahiro Kajino; Nobuhiro Inatomi |
Publication Detail:
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Type: In Vitro; Journal Article Date: 2010-07-12 |
Journal Detail:
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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:
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Created Date: 2010-09-21 Completed Date: 2010-10-21 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0376362 Medline TA: J Pharmacol Exp Ther Country: United States |
Other Details:
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Languages: eng Pagination: 231-8 Citation Subset: IM |
Affiliation:
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Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Osaka, Japan. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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2-Pyridinylmethylsulfinylbenzimidazoles
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pharmacology Animals Dithiothreitol / pharmacology Gastric Acid / secretion Gastric Mucosa / drug effects, enzymology, metabolism H(+)-K(+)-Exchanging ATPase / antagonists & inhibitors Histamine / pharmacology Hydrogen-Ion Concentration Imidazoles / pharmacology Kinetics Ligation Male Potassium / metabolism* Proton Pump Inhibitors / pharmacology* Pylorus Pyrroles / pharmacology* Rats Rats, Sprague-Dawley Stomach / chemistry Sulfonamides / pharmacology* Swine |
| Chemical | |
Reg. No./Substance:
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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 3.6.1.10/H(+)-K(+)-Exchanging ATPase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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