title: Development of 1,4-benzodiazepine cholecystokinin type B antagonists.
abstract: A series of 3-(arylureido)-5-phenyl-1,4-benzodiazepines, nonpeptidal antagonists of the peptide hormone cholecystokinin (CCK), are described. Derived by reasoned modification of the CCK-A selective 3-carboxamido-1,4-benzodiazepine, MK-329, this paper chronicles the development of potent, orally effective compounds in which selectivity for the CCK-B receptor subtype was achieved. The principal lead structure that emerged from these studied is L-365,260, a compound which has been submitted for clinical evaluation. Details of the ability to modulate the receptor interactions of these benzodiazepines by appropriate structure modifications are discussed which imply the possibility of further refining the CCK-B receptor affinity and selectivity of this class of compounds.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486.
authors.forename: M G
authors.initials: MG
authors.lastname: Bock
authors.forename: R M
authors.initials: RM
authors.lastname: DiPardo
authors.forename: B E
authors.initials: BE
authors.lastname: Evans
authors.forename: K E
authors.initials: KE
authors.lastname: Rittle
authors.forename: W L
authors.initials: WL
authors.lastname: Whitter
authors.forename: V M
authors.initials: VM
authors.lastname: Garsky
authors.forename: K F
authors.initials: KF
authors.lastname: Gilbert
authors.forename: J L
authors.initials: JL
authors.lastname: Leighton
authors.forename: K L
authors.initials: KL
authors.lastname: Carson
authors.forename: E C
authors.initials: EC
authors.lastname: Mellin
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001570:Benzodiazepinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D002540:Cerebral Cortex / Q000378:metabolism; D020109:Devazepide; D006168:Guinea Pigs; D015394:Molecular Structure; D010179:Pancreas / Q000378:metabolism; D010671:Phenylurea Compounds; D051381:Rats; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D012844:Sincalide / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D001570:Benzodiazepinones; D010671:Phenylurea Compounds; D011949:Receptors, Cholecystokinin; D001569:Benzodiazepines; C058121:L 365260; D020109:Devazepide; D012844:Sincalide