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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

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)

Pharmacodynamics Research Laboratories (K.I., K.K.), Pharmacology and Molecular Biology Research Laboratories (A.T., Y.M.-I., M.M.), and Biological Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan (F.I.); Licensing Department, Sankyo Co., Ltd., Nihonbashihonchou, Tokyo, Japan (K.T.); and Pharmaceutical Research Department, Ube Laboratory, Corporate Research & Development, Ube Industries, Ltd., Yamaguchi, Japan (N.S.)

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.

Address correspondence to: Keiichi Ito, Pharmacology Research Laboratories, Daiichi Sankyo, Co., Ltd., Hiromachi 1-2-58, Shinagawa-ku, Tokyo 140-8710, Japan. E-mail: ito.keiichi.vz{at}daiichisankyo.co.jp

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				K. Ito, K. Kinoshita, A. Tomizawa, Y. Morikawa-Inomata, F. Inaba, Y. Fujita, K. Tabata, and N. Shibakawa The Effect of Subchronic Administration of 7-(4-Fluorobenzyloxy)-2,3-dimethyl-1-{[(1S,2S)-2-methylcyclopropyl]methyl}-1H-pyrrolo[2,3-d]pyridazine (CS-526), a Novel Acid Pump Antagonist, on Gastric Acid Secretion and Gastrin Levels in Rats J. Pharmacol. Exp. Ther., July 1, 2008; 326(1): 163 - 170. [Abstract] [Full Text] [PDF]