TY - JOUR T1 - E3710, a New Proton Pump Inhibitor, with a Long-Lasting Inhibitory Effect on Gastric Acid Secretion JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 395 LP - 401 DO - 10.1124/jpet.110.167783 VL - 334 IS - 2 AU - Kotaro Kodama AU - Hideaki Fujisaki AU - Atsuhiko Kubota AU - Hiroshi Kato AU - Kazuo Hirota AU - Hiroko Kuramochi AU - Miki Murota AU - Yoshikuni Tabata AU - Masato Ueda AU - Hitoshi Harada AU - Tetsuya Kawahara AU - Masanobu Shinoda AU - Nobuhisa Watanabe AU - Daisuke Iida AU - Hiroki Terauchi AU - Sou Yasui AU - Shuhei Miyazawa AU - Junichi Nagakawa Y1 - 2010/08/01 UR - http://jpet.aspetjournals.org/content/334/2/395.abstract N2 - 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 IC50 of 0.28 μM. 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 ED50 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 (ED50 = 0.40 mg/kg) and 2.8 times more potent at 24 to 26 h (ED50 = 0.71 mg/kg). In the gastric fistula dogs, the intragastric pH was ≥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 ≥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. ER -