Development of Anti-ulcer Drug, Rebamipide.

A novel series of N-acylamino acid analogues of 2 (1H) -quinolinone was synthesized and evaluated for antiulcer activity against acetic acid-induced gastric ulcer in rats. Out of this investigation, 2- (4-chlorobenzoylamino) -3- [2 (1H) -quinolinon-4-yl] propionic acid (rebamipide, OPC-12759) was identified The structureactivity relationships are discussed.Rebamipide did not only increase the healing rate of a chronic gastric ulcer model, acetic acid-induced gastric ulcer in rats, but also prevented recurrence and/or relapse of the ulcer in long term observation Rebamipide inhibited the formation of gastric mucosal lesions induced by various conditions. Rebamipide did not inhibit gastric acid secretion, although it potentiated gastric mucosal defensive factors such as mucus secretion, alkaline secretion, gastric mucosal blood flow and mucosal barrier. Rebamipide inhibited ethanol-induced gastric mucosal necrosis, which was completely abolished by pretreatment with indomethacin, suggesting the mucosal protective effect is associated with endogenous prostaglandins. Rebamipide inhibited production of superoxide from polymorphonuclear leukocytes and scavenged hydroxyl radical in vitro. Rebamipide showed useful efficacy on Helicobacter pylori-induced cell damage associated with activated neutrophils.The enantiomers of rebamipide were synthesized by using three efficient methods. Both enantiomers showed anti-ulcer activity against acetic acid-induced gastric ulcer and EtOH-induced gastric ulcer. The pair of enantiomers showed a small difference in activity.