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.
Kodama
Kotaro
K
Tsukuba Research Laboratories, Eisai Co, Ltd, 1-3 Tokodai 5-Choume, Tsukuba-shi 300-2635, Ibaraki, Japan. k-kodama@hhc.eisai.co.jp
Fujisaki
Hideaki
H
Kubota
Atsuhiko
A
Kato
Hiroshi
H
Hirota
Kazuo
K
Kuramochi
Hiroko
H
Murota
Miki
M
Tabata
Yoshikuni
Y
Ueda
Masato
M
Harada
Hitoshi
H
Kawahara
Tetsuya
T
Shinoda
Masanobu
M
Watanabe
Nobuhisa
N
Iida
Daisuke
D
Terauchi
Hiroki
H
Yasui
Sou
S
Miyazawa
Shuhei
S
Nagakawa
Junichi
J
D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology; D004285:Dogs; D064098:Esomeprazole / Q000494:pharmacology; D005744:Gastric Acid / Q000378:metabolism*; D005753:Gastric Mucosa / Q000187:drug effects / Q000201:enzymology; D006632:Histamine / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D008297:Male; D054328:Proton Pump Inhibitors / Q000494:pharmacology*; D011817:Rabbits; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors; D013454:Sulfoxides / Q000494:pharmacology*; D013552:Swine
C551467:2-(4-(2,2-dimethyl-1,3-dioxan-5-yl)methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl-1H-benzimidazole; D001562:Benzimidazoles; D054328:Proton Pump Inhibitors; D013454:Sulfoxides; D006632:Histamine; D000254:Sodium-Potassium-Exchanging ATPase; D064098:Esomeprazole