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

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 334; no. 2; p. 395
• Main Authors: Kodama, Kotaro, Fujisaki, Hideaki, Kubota, Atsuhiko, Kato, Hiroshi, Hirota, Kazuo, Kuramochi, Hiroko, Murota, Miki, Tabata, Yoshikuni, Ueda, Masato, Harada, Hitoshi, Kawahara, Tetsuya, Shinoda, Masanobu, Watanabe, Nobuhisa, Iida, Daisuke, Terauchi, Hiroki, Yasui, Sou, Miyazawa, Shuhei, Nagakawa, Junichi
• Format: Journal Article
• Language: English
• Published: United States 01-08-2010
• Subjects: Animals; Benzimidazoles - pharmacology; Cerebral Cortex - drug effects; Cerebral Cortex - enzymology; Dogs; Esomeprazole - pharmacology; Gastric Acid - secretion; Gastric Mucosa - drug effects; Gastric Mucosa - enzymology; Histamine - pharmacology; Hydrogen-Ion Concentration; Male; Proton Pump Inhibitors - pharmacology; Rabbits; Sodium-Potassium-Exchanging ATPase - antagonists & inhibitors; Sulfoxides - pharmacology; Swine
• ISSN: 1521-0103
• DOI: 10.1124/jpet.110.167783

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.