Pharmacological profile of novel acid pump antagonist 7-(4-fluorobenzyloxy)-2,3-dimethyl-1-{[(1S,2S)-2-methyl cyclopropyl]methyl}-1H-pyrrolo[2,3-d]pyridazine (CS-526)
| Autor: | Shibakawa Nobuhiko, Keiichi Tabata, Fumi Inaba, Atsuyuki Tomizawa, Kazuya Kinoshita, Yuka Morikawa-Inomata, Mitsuko Makino, Keiichi Ito |
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| Rok vydání: | 2007 |
| Předmět: |
Male
Swine Lansoprazole Pharmacology Kidney Pyridazine Gastric Acid Rats Sprague-Dawley chemistry.chemical_compound Dogs Gastrointestinal Agents Oral administration Medicine Animals Pyrroles Stomach Ulcer Reflux esophagitis Enzyme Inhibitors IC50 Esophagitis Peptic Molecular Structure business.industry Antagonist Proton Pump Inhibitors Rats Pyridazines Disease Models Animal chemistry Biochemistry Gastric Mucosa Molecular Medicine Gastric acid business Antagonism medicine.drug |
| Zdroj: | The Journal of pharmacology and experimental therapeutics. 323(1) |
| ISSN: | 0022-3565 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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