Effects of S-0509, a novel CCKB/gastrin receptor antagonist, on acid secretion and experimental duodenal ulcers in rats

Background: S-0509, 2-[(tert-butoxycarbonylmethyl) [(m-(carboxy-phenyl)-ure idomethyl-carbonyl]] aminobenzo phenone, was developed as a potent and sele ctive CCKB/ gastrin receptor antagonist that does not affect the central ne rvous system. Methods: We evaluated the effects of S-0509 on gastric acid secretion and d uodenal ulcerogenic and healing responses in rats comparing it with L-365,2 60, another CCKB/gastrin receptor antagonist. Results: S-0509 (0.1 similar to 10 mg/kg, i.d.) was able to dose-dependentl y decrease basal acid secretion and inhibit the acid secretory responses in duced by both pentagastrin (60 mu g/kg/h, i.v.) and peptone (10%, i.g.) but not histamine (4 mg/kg/hr, i.v.) or carbachol (60 mu g/kg/h. i.v.). L-365, 260 (10 and 30 mg/kg, i.d.). caused only partial a suppression of the acid secretory response to pentagastrin but not to other stimuli, including pept one treatment. On the other hand, a duodenal ulcerogen, mepirizole (200 mg/ kg, s.c.) caused an increase in acid secretion and resulted in penetrating ulcers in the proximal duodenum, and these ulcers gradually healed over 3 w eeks. S-0509 significantly inhibited both the acid secretory (> 1.0 mg/kg, i.d.) and ulcerogenic (> 3 mg/kg, p.o.) responses induced by mepirizole whe n it was given as a pre-treatment. It also promoted significantly the heali ng of these ulcers (> 3 x 2 mg/kg, p.o.) when it was given twice daily for 14 days. In contrast, L-365,260 (30 mg/ kg) tended to reduce the severity o f mepirizole-induced duodenal ulcers, with a slight inhibition of acid secr etion, but it caused no influence on the healing response of these ulcers. Conclusion: These results confirmed that S-0509 is a selective CCKB/gastrin receptor antagonist with potent antisecretory action in vivo conditions, a nd further demonstrated that this agent not only prevents the development o f duodenal ulcers but also shows healing promoting action on duodenal ulcer s, probably through the blockade of CCKB/gastrin receptors.