RT Journal Article
SR Electronic
T1 Pharmacological Profile of Novel Acid Pump Antagonist 7-(4-Fluorobenzyloxy)-2,3-dimethyl-1-{[(1<em>S</em>,2<em>S</em>)-2-methyl cyclopropyl]methyl}-1<em>H</em>-pyrrolo[2,3-<em>d</em>]pyridazine (CS-526)
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 308
OP 317
DO 10.1124/jpet.107.121350
VO 323
IS 1
A1 Ito, Keiichi
A1 Kinoshita, Kazuya
A1 Tomizawa, Atsuyuki
A1 Inaba, Fumi
A1 Morikawa-Inomata, Yuka
A1 Makino, Mitsuko
A1 Tabata, Keiichi
A1 Shibakawa, Nobuhiko
YR 2007
UL http://jpet.aspetjournals.org/content/323/1/308.abstract
AB The pharmacological profiles of the novel acid pump antagonist 7-(4-fluorobenzyloxy)-2,3-dimethyl-1-{[(1S,2S)-2-methylcyclopropyl]methyl}-1H-pyrrolo[2,3-d]pyridazine (CS-526) were investigated in terms of hog gastric H+,K+-ATPase activity, gastric acid secretion, and acute gastroesophageal lesions in comparison with other proton pump inhibitors (PPIs). CS-526 inhibited H+,K+-ATPase activity in a concentration-dependent manner, with an IC50 value of 61 nM. The inhibitory effect of CS-526 on H+,K+-ATPase activity was more potent than that of any of the other PPIs examined. The inhibitory mechanism of CS-526 on H+,K+-ATPase was a competitive antagonism to the K+ binding site of H+,K+-ATPase, and it was also a reversible inhibition. In pylorus-ligated rats, intraduodenal or oral administration of CS-526 inhibited gastric acid secretion in a dose-dependent manner, and the ID50 values were 2.8 or 0.7 mg/kg, respectively. In Heidenhain pouch dogs, intrapouch administration of CS-526 inhibited histamine-stimulated gastric acid secretion in a dose- and retention time-dependent manner. In a reflux esophagitis model, intraduodenal and oral administration of CS-526 prevented esophageal lesions with ID50 values of 5.4 and 1.9 mg/kg, respectively. Lansoprazole prevented esophagitis only by intraduodenal administration (ID50 = 2.2 mg/kg). Furthermore, CS-526 inhibited acute gastric mucosal lesions. These data demonstrate that the novel acid pump antagonist CS-526 has potent antisecretory and antiulcer effects. These findings indicate that CS-526 would have a curative effect on gastroesophageal reflux disease via its potent antisecretory and antiulcer actions. The American Society for Pharmacology and Experimental Therapeutics