PMID- 20484556
OWN - NLM
STAT- MEDLINE
DCOM- 20100817
LR  - 20220318
IS  - 1521-0103 (Electronic)
IS  - 0022-3565 (Linking)
VI  - 334
IP  - 2
DP  - 2010 Aug
TI  - E3710, a new proton pump inhibitor, with a long-lasting inhibitory effect on 
      gastric acid secretion.
PG  - 395-401
LID - 10.1124/jpet.110.167783 [doi]
AB  - 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.
FAU - Kodama, Kotaro
AU  - Kodama K
AD  - Tsukuba Research Laboratories, Eisai Co, Ltd, 1-3 Tokodai 5-Choume, Tsukuba-shi 
      300-2635, Ibaraki, Japan. k-kodama@hhc.eisai.co.jp
FAU - Fujisaki, Hideaki
AU  - Fujisaki H
FAU - Kubota, Atsuhiko
AU  - Kubota A
FAU - Kato, Hiroshi
AU  - Kato H
FAU - Hirota, Kazuo
AU  - Hirota K
FAU - Kuramochi, Hiroko
AU  - Kuramochi H
FAU - Murota, Miki
AU  - Murota M
FAU - Tabata, Yoshikuni
AU  - Tabata Y
FAU - Ueda, Masato
AU  - Ueda M
FAU - Harada, Hitoshi
AU  - Harada H
FAU - Kawahara, Tetsuya
AU  - Kawahara T
FAU - Shinoda, Masanobu
AU  - Shinoda M
FAU - Watanabe, Nobuhisa
AU  - Watanabe N
FAU - Iida, Daisuke
AU  - Iida D
FAU - Terauchi, Hiroki
AU  - Terauchi H
FAU - Yasui, Sou
AU  - Yasui S
FAU - Miyazawa, Shuhei
AU  - Miyazawa S
FAU - Nagakawa, Junichi
AU  - Nagakawa J
LA  - eng
PT  - Journal Article
DEP - 20100519
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
RN  - 0 
      (2-(4-(2,2-dimethyl-1,3-dioxan-5-yl)methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl-1H-benzimidazole)
RN  - 0 (Benzimidazoles)
RN  - 0 (Proton Pump Inhibitors)
RN  - 0 (Sulfoxides)
RN  - 820484N8I3 (Histamine)
RN  - EC 7.2.2.13 (Sodium-Potassium-Exchanging ATPase)
RN  - N3PA6559FT (Esomeprazole)
SB  - IM
MH  - Animals
MH  - Benzimidazoles/*pharmacology
MH  - Cerebral Cortex/drug effects/enzymology
MH  - Dogs
MH  - Esomeprazole/pharmacology
MH  - Gastric Acid/*metabolism
MH  - Gastric Mucosa/drug effects/enzymology
MH  - Histamine/pharmacology
MH  - Hydrogen-Ion Concentration
MH  - Male
MH  - Proton Pump Inhibitors/*pharmacology
MH  - Rabbits
MH  - Sodium-Potassium-Exchanging ATPase/antagonists & inhibitors
MH  - Sulfoxides/*pharmacology
MH  - Swine
EDAT- 2010/05/21 06:00
MHDA- 2010/08/18 06:00
CRDT- 2010/05/21 06:00
PHST- 2010/05/21 06:00 [entrez]
PHST- 2010/05/21 06:00 [pubmed]
PHST- 2010/08/18 06:00 [medline]
AID - jpet.110.167783 [pii]
AID - 10.1124/jpet.110.167783 [doi]
PST - ppublish
SO  - J Pharmacol Exp Ther. 2010 Aug;334(2):395-401. doi: 10.1124/jpet.110.167783. Epub 
      2010 May 19.