E3710, a new proton pump inhibitor, with a long-lasting inhibitory effect on gastric acid secretion.

We have investigated the pharmacology of sodium (R)-2-[4-(2,2-dimethyl-1,3-dioxan-5-yl) methoxy-3,5-dimethylpyridin-2-yl]methylsulfinyl-1H-benzimidazol (E3710), a new proton pump inhibitor (PPI), and its effect on gastric acid secretion. E3710 irreversibly inhibited H(+),K(+)-ATPase activity in pig gastric vesicles with an acidic internal environment with an IC(50) of 0.28 microM. Administration of E3710 (0.1, 0.2, 0.4, and 0.8 mg/kg; n = 6) intraduodenally in a gastric fistula model in dogs inhibited histamine-stimulated gastric acid secretion at 0 to 2 and 24 to 26 h after administration with ED(50) values of 0.18 and 0.22 mg/kg, respectively. The inhibition by E3710 was 2.3 times more potent than that of another representative PPI, esomeprazole (0.2, 0.4, 0.8, and 1.6 mg/kg; n = 6) at 0 to 2 h after administration (ED(50) = 0.40 mg/kg) and 2.8 times more potent at 24 to 26 h (ED(50) = 0.71 mg/kg). In the gastric fistula dogs, the intragastric pH was >or=4 for 17% (n = 27) of a 24-h period with vehicle alone, but when E3710 was administered, at 0.2 (n = 4), 0.4 (n = 8), and 0.8 mg/kg (n = 5), the pH was >or=4 for 40, 79, and 88% of a day, respectively. The corresponding values for esomeprazole at 0.8 (n = 4) and 1.6 mg/kg (n = 8) were 55 and 59%, respectively. In a crossover study with vehicle, E3710 at 0.4 mg/kg and esomeprazole at 1.6 mg/kg (n = 6), E3710 increased the intragastric pH to >4 for 82% of a day compared with 61% of a day with esomeprazole. These results show that E3710 is a long-acting inhibitor of gastric acid secretion and a promising novel therapy for acid-related diseases, such as gastroesophageal reflux disease.
AuthorsKotaro Kodama, Hideaki Fujisaki, Atsuhiko Kubota, Hiroshi Kato, Kazuo Hirota, Hiroko Kuramochi, Miki Murota, Yoshikuni Tabata, Masato Ueda, Hitoshi Harada, Tetsuya Kawahara, Masanobu Shinoda, Nobuhisa Watanabe, Daisuke Iida, Hiroki Terauchi, Sou Yasui, Shuhei Miyazawa, Junichi Nagakawa
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 334 Issue 2 Pg. 395-401 (Aug 2010) ISSN: 1521-0103 [Electronic] United States
PMID20484556 (Publication Type: Journal Article)
Chemical References
  • 2-(4-(2,2-dimethyl-1,3-dioxan-5-yl)methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl-1H-benzimidazole
  • Benzimidazoles
  • Proton Pump Inhibitors
  • Sulfoxides
  • Histamine
  • Sodium-Potassium-Exchanging ATPase
  • Esomeprazole
  • Animals
  • Benzimidazoles (pharmacology)
  • Cerebral Cortex (drug effects, enzymology)
  • Dogs
  • Esomeprazole (pharmacology)
  • Gastric Acid (secretion)
  • Gastric Mucosa (drug effects, enzymology)
  • Histamine (pharmacology)
  • Hydrogen-Ion Concentration
  • Male
  • Proton Pump Inhibitors (pharmacology)
  • Rabbits
  • Sodium-Potassium-Exchanging ATPase (antagonists & inhibitors)
  • Sulfoxides (pharmacology)
  • Swine

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