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

Abstract

Background: S‐0509, 2‐[(tert‐butoxycarbonylmethyl) [(m‐(carboxy‐phenyl)‐ureidomethyl‐carbonyl]] aminobenzo phenone, was developed as a potent and selective CCKB/gastrin receptor antagonist that does not affect the central nervous system. Methods: We evaluated the effects of S‐0509 on gastric acid secretion and duodenal ulcerogenic and healing responses in rats comparing it with L‐365,260, another CCKB/gastrin receptor antagonist. Results: S‐0509 (0.1~10 mg/kg, i.d.) was able to dose‐dependently decrease basal acid secretion and inhibit the acid secretory responses induced by both pentagastrin (60 μg/kg/h, i.v.) and peptone (10%, i.g.) but not histamine (4 mg/kg/hr, i.v.) or carbachol (60 μg/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 peptone 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 weeks. 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 when it was given as a pre‐treatment. It also promoted significantly the healing of these ulcers (> 3 × 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 of mepirizole‐induced duodenal ulcers, with a slight inhibition of acid secretion, 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, and further demonstrated that this agent not only prevents the development of duodenal ulcers but also shows healing promoting action on duodenal ulcers, probably through the blockade of CCKB/gastrin receptors.

Selective action of a CCK‐B/gastrin receptor antagonist, S‐0509, on pentagastrin‐, peptone meal‐ and beer‐stimulated gastric acid secretion in dogs

“…In contrast, Takeuchi et al . recently reported that S‐0509 had no effect on carbachol‐stimulated gastric acid secretion in anesthetized rats 13 . Consequently, we examined the effectiveness of S‐0509 on gastric acid secretion in dogs as a selective gastrin antagonist.…”

Gastric acid secretion in dogs in response to combinations of beer, ethanol and peptone meal – the role of endogenous gastrin

“… 7 In terms of pharmacological studies, it has been shown in animal studies that selective cholecystokinin‐B/gastrin receptor antagonists, such as YM022, YF476 or S‐0509, extensively inhibit gastric acid secretion in response to peptone or beer. 8–13 To our knowledge, however, no data have been reported detailing the effects of the combination of peptone and beer, which may result in a much stronger stimulation of acid secretion.…”

Developments in the inhibition of gastric acid secretion

“…L‐365260 has a poor bioavailability, a very short half‐life, and is ineffective in inhibiting basal acid secretion. Compared with the H 2 RA famotidine, YM‐022 was equally effective in rats in preventing indomethacin‐induced ulcers, but it is no longer clinically developed owing to the development of tachyphylaxis [21]. Agents currently in development include Z‐360 and itriglumide.…”