title: Dual CCK-A and CCK-B receptor antagonists (II). Preparation and structure activity relationships of 5-alkyl-9-methyl-1,4-benzodiazepines and discovery of FR208419.
abstract: In our continuing research for dual CCK-A and -B antagonists, according to our hypothesis that dual CCK-A and -B antagonists should be more efficacious than selective CCK-A antagonists for the treatment of pancreatitis, we have prepared various 5-alkyl-9-methyl-1,4-benzodiazepines. From the compounds prepared, 1-cyclohexyl-carbonylmethyl-5-ethyl-9-methyl-3- (m-tolylureido)-2-oxo-1,4-benzodiazepine, (40) was selected as a candidate for development due to its well-balanced high affinity for both receptors. The R-enantiomer of 40, (R)-40 (FR 208419), had 27-fold higher affinity for the CCK-A receptor and 8-fold more potent CCK-B receptor binding activity than (S)-40. The biological activity after p.o. administration of (R)-40, estimated from the ID50 value (0.23 mg/kg p.o.) obtained by preliminary evaluation by gastric emptying effects, is considered to be high enough for further development. This compound is now undergoing further biological evaluations with a view to clinical development.
authors.affiliation: Medicinal Chemistry Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Tabuchi
authors.forename: H
authors.initials: H
authors.lastname: Ito
authors.forename: H
authors.initials: H
authors.lastname: Sogabe
authors.forename: M
authors.initials: M
authors.lastname: Kuno
authors.forename: T
authors.initials: T
authors.lastname: Kinoshita
authors.forename: I
authors.initials: I
authors.lastname: Katumi
authors.forename: N
authors.initials: N
authors.lastname: Yamamoto
authors.forename: H
authors.initials: H
authors.lastname: Mitsui
authors.forename: Y
authors.initials: Y
authors.lastname: Satoh
mesh_terms: D000818:Animals; D001570:Benzodiazepinones / Q000138:chemical synthesis* / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D005746:Gastric Emptying / Q000187:drug effects; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism; D010671:Phenylurea Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D043886:Receptor, Cholecystokinin A; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D012844:Sincalide / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D001570:Benzodiazepinones; C406430:FR 208419; D007202:Indicators and Reagents; D010671:Phenylurea Compounds; D043886:Receptor, Cholecystokinin A; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; D012844:Sincalide