title: 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).
abstract: 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.
authors.affiliation: Pharmacology Research Laboratories, Daiichi Sankyo, Co., Ltd., Hiromachi 1-2-58, Tokyo 140-8710, Japan. ito.keiichi.vz@daiichisankyo.co.jp
authors.forename: Keiichi
authors.initials: K
authors.lastname: Ito
authors.forename: Kazuya
authors.initials: K
authors.lastname: Kinoshita
authors.forename: Atsuyuki
authors.initials: A
authors.lastname: Tomizawa
authors.forename: Fumi
authors.initials: F
authors.lastname: Inaba
authors.forename: Yuka
authors.initials: Y
authors.lastname: Morikawa-Inomata
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Makino
authors.forename: Keiichi
authors.initials: K
authors.lastname: Tabata
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Shibakawa
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004285:Dogs; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004942:Esophagitis, Peptic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D005744:Gastric Acid / Q000378:metabolism*; D005753:Gastric Mucosa / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D005765:Gastrointestinal Agents / Q000737:chemistry / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D008297:Male; D015394:Molecular Structure; D054328:Proton Pump Inhibitors; D011724:Pyridazines / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013276:Stomach Ulcer / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D013552:Swine
chemical_list: C523982:7-(4-fluorobenzyloxy)-2,3-dimethyl-1-((2-methylcyclopropyl)methyl)-1H-pyrrolo(2,3-d)pyridazine; D004791:Enzyme Inhibitors; D005765:Gastrointestinal Agents; D054328:Proton Pump Inhibitors; D011724:Pyridazines; D011758:Pyrroles