pyrimidinones and roxatidine-acetate

The effects of IGN-2098 on the healing process of acetic acid-induced gastric ulcer was investigated in comparison with the other histamine H2-receptor antagonists, famotidine and roxatidine acetate HCl, in rats. Ulcer was induced by the injection of acetic acid solution (20%, 0.05 ml). From the 4th day to 17th day after the ulcer induction, drugs were orally administered twice a day. On the 18th day after the ulcer induction, rats were sacrificed to measure the ulcer index macroscopically and to take pictures of the stomachs. Judging from the photographs, the prominence of ulcer the edge was graded into 4 classes, which showed a significant correlation with the histological amount of connective tissue at the ulcer edge. All drugs accelerated the healing of the ulcer, and the effect of IGN-2098 was the most remarkable. In addition, IGN-2098-treatment exhibited more marked inhibition against the prominence of the ulcer edge as compared with the control group. Based on these results, it is concluded that IGN-2098 may be a useful drug for the clinical treatment of ulcer and that the healing acceleration by IGN-2098 without prominence of the ulcer edge may induce no relapse of the ulcer after healing.

Topics: Acetates; Acetic Acid; Animals; Anti-Ulcer Agents; Famotidine; Histamine H2 Antagonists; Male; Piperidines; Pyrimidinones; Rats; Rats, Sprague-Dawley; Stomach Ulcer

Effects of IGN-2098 (5,6-dimethyl-2-[4-[3-(1-piperidinomethyl)phenoxy]- (z)-2-butenylamino]-4(1H)-pyrimidone dihydrochloride, CAS 126869-04-3) a novel histamine H2-antagonist, on histamine-induced gastric acid secretion were investigated in Heidenhain pouch dogs in comparison with those of famotidine, roxatidine acetate HCl and cimetidine. Orally administered IGN-2098 (0.03-1.0 mg/kg), famotidine (0.01-0.3 mg/kg), roxatidine acetate HCl (0.1-1.0 mg/kg) and cimetidine (0.3-3.0 mg/kg) showed dose-dependent inhibition on histamine-induced gastric acid secretion, and ED50 values of IGN-2098, famotidine, roxatidine acetate HCl and cimetidine were 0.077, 0.024, 0.200 and 0.585 mg/kg, respectively. IGN-2098 was effective even at 6 h after administration and ED50 value was 0.315 mg/kg. IGN-2098 was effective also by intravenous route. The inhibitory effect of IGN-2098 on histamine-induced gastric secretion was not affected by the repeated administration of IGN-2098 (1 mg/kg b.i.d. for 14 days). These results show that IGN-2098 is a potent and long acting antisecretory agent and is a useful antisecretory drug for the treatment of peptic ulcer disease.

Topics: Administration, Oral; Animals; Cimetidine; Dogs; Dose-Response Relationship, Drug; Famotidine; Gastric Acid; Gastric Mucosa; Histamine; Histamine H2 Antagonists; Injections, Intravenous; Male; Piperidines; Pyrimidinones

A new compound, IGN-2098 [5,6-dimethyl-2-[4-<3-(1-piperidinomethyl) phenoxy>cis-butenylamino]-4-(1H)-pyrimidone.2HCl], was found to be a potential histamine H2-receptor antagonist in the guinea pig atrium. IGN-2098, given p.o., significantly and persistently (for more than 12 hr) inhibited the basal gastric secretion in pylorus-ligated rats. The agent also significantly inhibited the basal gastric secretion when given by the s.c.-, i.d.- or i.p.-route. Stimulated gastric secretion in fistula rats in response to histamine, carbachol or pentagastrin was also significantly inhibited with IGN-2098 given s.c. Pretreatment with IGN-2098 (p.o.) significantly protected the gastric mucosa against pylorus ligation-, water-immersion stress-, histamine-, indomethacin-, HCl.aspirin-, and HCl.ethanol-induced gastric lesions. In addition, the agent significantly protected the duodenal mucosa against mepirizole-induced ulcers. Based upon the ED50 values, the antisecretory effects on histamine, carbachol or pentagastrin-stimulated acid secretion were 6.0, 37.0 or 80 times more potent than roxatidine, respectively. As to the anti-lesion effects on HCl.aspirin-induced gastric lesions or mepirizole-induced duodenal ulcers, IGN-2098 was 8.1 or 14.8 times more potent than roxatidine, respectively. These results suggest that IGN-2098 will be a useful drug for the treatment of gastric and duodenal lesions in man.

Topics: Animals; Anti-Ulcer Agents; Dose-Response Relationship, Drug; Duodenal Ulcer; Gastric Juice; Histamine H2 Antagonists; Male; Piperidines; Pyrimidinones; Rats; Rats, Inbred Strains; Stomach Ulcer