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:
S-0509 (0.1 approximately 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 microg/kg/h, i.v.) and
peptone (10%, i.g.) but not
histamine (4 mg/kg/hr, i.v.) or
carbachol (60 microg/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 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 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.