SYNTHESIS AND PHARMACOLOGICAL PROPERTIES OF UREIDOMETHYLCARBAMOYLPHENYLKETONE DERIVATIVES - A NEW POTENT AND SUBTYPE-SELECTIVE NONPEPTIDE CCK-B GASTRIN RECEPTOR ANTAGONIST, S-0509/

A novel series of CCK-B/gastrin receptor antagonists-ureidomethylcarba moylphenylketone derivatives were designed, synthesized, and evaluated for activity. Structure-activity relationship studies revealed the im portance of a carboxylic acid at substituent R-2 and a tert-butoxycarb onyl group at R-1 in structure A. Compound 7a (S-0509) showed remarkab le affinity for the CCK-B/gastrin receptor and a subtype selectivity p rofile in vitro. Administration (id) of 7a led to excellent inhibition of gastric acid secretion induced by pentagastrin in anesthetized rat s with an ED50 value of 0.014 mg/kg. Furthermore, 7a proved to have po or blood-brain permeability by its small effect on enhancement of morp hine analgesia. Thus, S-0509 has an increase in selectivity for the pe ripheral effects of gastrin antagonism from the central effects of CCK -B antagonism. (C) 1997 Elsevier Science Ltd.