BENZODIAZEPIN-3-YL)-N'-(3-(METHYLAMINO)PHENYL)UREA (YF476) - A POTENTAND ORALLY-ACTIVE GASTRIN CCK-B ANTAGONIST/

A number of new 1,4-benzodiazepin-2-one-based gastrin/CCK-B receptor a ntagonists related to the archetypal analogue L-365,260, and more clos ely to the recently reported compound YM022, have been synthesized and evaluated for biological activity. The compounds were screened for th eir ability to inhibit the binding of [I-125]CCK-8 to gastrin/CCK-B re ceptors prepared from rat brains and that of [H-3]L-364,718 to CCK-A r eceptors from rat pancreas, and were shown to be potent and selective ligands for the gastrin/CCK-B receptor. Functional studies in vivo dem onstrated the compounds to be antagonists of the receptor as evidenced by their ability to inhibit pentagastrin-induced gastric acid secreti on in anesthetized rats. More extensive evaluation in vivo included de termination of ED(50) values in the rat acid secretion model for selec ted compounds and an examination of the effect of these compounds on p entagastrin-induced gastric acid secretion in Heidenhain pouch. dogs f ollowing oval and intravenous administration. Two compounds, i.e. enzo diazepin-3-yl]-N'-[3-(methylamino)phenyl]urea, 15c (YF476), and nzodia zepin-3-yl]-N'-[3-(dimethylamino)phenyl]urea hydrochloride, 15d, showe d potent dose-dependent effects in both models with the former showing excellent oral bioavailability and an ED(50) of 21nmol/kg po in dogs. 15c is currently under clinical investigation for the treatment of ga stro-oesophagal reflux disease (GORD).