Ito Keiichi, Kinoshita Kazuya, Tomizawa Atsuyuki, Inaba Fumi, Morikawa-Inomata Yuka, Makino Mitsuko, Tabata Keiichi, Shibakawa Nobuhiko
Pharmacology Research Laboratories, Daiichi Sankyo, Co., Ltd., Hiromachi 1-2-58, Tokyo 140-8710, Japan.
J Pharmacol Exp Ther. 2007 Oct;323(1):308-17. doi: 10.1124/jpet.107.121350. Epub 2007 Jul 13.
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.
与其他质子泵抑制剂（PPI）相比，研究了新型酸泵拮抗剂7-(4-氟苄氧基)-2,3-二甲基-1-{[(1S,2S)-2-甲基环丙基]甲基}-1H-吡咯并[2,3-d]哒嗪（CS-526）在猪胃H⁺,K⁺-ATP酶活性、胃酸分泌及急性胃食管损伤方面的药理学特性。CS-526以浓度依赖方式抑制H⁺,K⁺-ATP酶活性，IC50值为61 nM。CS-526对H⁺,K⁺-ATP酶活性的抑制作用比所检测的任何其他PPI都更强。CS-526对H⁺,K⁺-ATP酶的抑制机制是对H⁺,K⁺-ATP酶的K⁺结合位点的竞争性拮抗，并且也是可逆性抑制。在幽门结扎大鼠中，十二指肠内或口服CS-526以剂量依赖方式抑制胃酸分泌，ID50值分别为2.8或0.7 mg/kg。在海登海因小胃犬中，胃内给予CS-526以剂量和滞留时间依赖方式抑制组胺刺激的胃酸分泌。在反流性食管炎模型中，十二指肠内和口服CS-526预防食管损伤，ID50值分别为5.4和1.9 mg/kg。兰索拉唑仅通过十二指肠内给药预防食管炎（ID50 = 2.2 mg/kg）。此外，CS-526抑制急性胃黏膜损伤。这些数据表明新型酸泵拮抗剂CS-526具有强效的抗分泌和抗溃疡作用。这些发现表明CS-526通过其强效的抗分泌和抗溃疡作用对胃食管反流病具有治疗作用。
