The pharmacological profile of N-[3-[2-[N'-(2-methoxyethyl)guanidino]thiazol-4yl]benzyl-ace tamide (
FR145715), a novel
histamine H2 receptor antagonist, was examined in both in vitro and in vivo models using experimental animals in comparison with
ranitidine. In isolated guinea-pig atria,
FR145715 antagonized the effect of
histamine on heart rate with approximately three times more potent activity than
ranitidine. In in vivo experiments, intraduodenal
FR145715 dose-dependently inhibited spontaneous gastric acid secretion in rats (Shay's rats), with a ED50 value of 18.4 mg/kg, which was comparable to that of
ranitidine (30.5 mg/kg).
FR145715 also inhibited
histamine-stimulated
acid secretion in stomach-perfused anaesthetized rats (Schild's rats), when given intravenously and intraduodenally with ED50 values of 0.59 and 2.72 mg/kg, respectively.
Ranitidine displayed more potent activity having respective ED50 values of 0.10 and 0.17 mg/kg. In Heidenhain pouch dogs, intravenous and oral
FR145715 dose-dependently inhibited
gastrin-stimulated
acid secretion with respective ED50 values of 0.12 and 0.32 mg/kg, which were similar to those of
ranitidine (0.09 and 0.33 mg/kg). In
gastric ulcer models,
FR145715 dose-dependently inhibited water immersion restraint stress- and acidified
aspirin-induced gastric lesions with ED50 values of 3.2 and 15.1 mg/kg (p.o.), respectively. The comparative compound,
ranitidine, also showed beneficial effects on stress-induced
gastric ulcers with an ED50 value of 1.5 mg/kg (p.o.). However, it failed to inhibit acidified
aspirin-induced
gastric ulcers.
FR145715 inhibited HCl-induced gastric lesions in rats, while pre-treatment with
indomethacin abolished its beneficial effects, suggesting that
FR145715 has a so-called cytoprotective effect which is dependent on endogenous
prostaglandin production. In addition to its atypical profile as a
histamine H2 receptor antagonist,
FR145715 exhibited strong anti-microbial activities against strains of Helicobacter pylori (H. pylori) with a mean minimal inhibitory concentration value of 0.32 microg/ml. Moreover,
FR145715 showed no anti-microbial effects on 25 other bacteria examined. In addition, in vivo experiments using gnotobiotic piglets infected with H. pylori,
FR145715 (16 mg/kg, t.i.d.) completely eliminated the organism with reduced intensity of
inflammation, when treated orally for 10 days. These data demonstrate that
FR145715 is a novel
histamine H2 receptor antagonist having potent and selective anti-H. pylori activities as well as cytoprotective properties. The present data suggest that
FR145715 might be useful for the patients suffering from
ulcer relapse, since the
drug might be able to eradicate H. pylori in the stomach, which is considered a key factor to cause
ulcer recurrence in humans.