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

• Published in: Chemical & pharmaceutical bulletin Vol. 48; no. 1; pp. 1 - 15
• Main Authors: TABUCHI, Seiichiro, ITO, Harunobu, SOGABE, Hajime, KUNO, Masako, KINOSHITA, Takayoshi, TATUMI, Ikuyo, YAMAMOTO, Naoko, MITSUI, Hitoshi, SATOH, Yoshinari
• Format: Journal Article
• Language: English
• Published: TOKYO The Pharmaceutical Society of Japan 01.01.2000; Pharmaceutical Soc Japan; Maruzen; Japan Science and Technology Agency
• Subjects: (3R)-1-cyclohexylcarbonyl-methyl-5-ethyl-9-methyl-2-oxo-[3-(m-tolyl)ureido]-1, 4-benzodiazepine; 5-alkyl-9-methyl-1, 4-benzodiazepine; Animals; Benzodiazepinones - chemical synthesis; Benzodiazepinones - pharmacology; Biological and medical sciences; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; Digestive system; dual CCK-A and -B antagonist; Gastric Emptying - drug effects; Guinea Pigs; In Vitro Techniques; Indicators and Reagents; Life Sciences & Biomedicine; Magnetic Resonance Spectroscopy; Medical sciences; Mice; Models, Molecular; Pancreas - drug effects; Pancreas - metabolism; pancreatitis; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Phenylurea Compounds - chemical synthesis; Phenylurea Compounds - pharmacology; Physical Sciences; Rats; Receptor, Cholecystokinin A; Receptor, Cholecystokinin B; Receptors, Cholecystokinin - antagonists & inhibitors; Science & Technology; Sincalide - metabolism; Stereoisomerism; Structure-Activity Relationship; 5-alkyl-9-methyl-1,4-benzodiazepine; ANILINES; RESOLUTION; dual CCK-A and -B antagonist; pancreatitis; FK480; (3R)-1-cyclohexylcarbonyl methyl-5-ethyl-9-methyl-2-oxo-[3-(m-tolyl)ureido]-1,4-benzodiazepine; Enantioselectivity; Rat; Nitrogen heterocycle; Central nervous system; Lactam; Non peptide compound; Selectivity; Guinea pig; Structure activity relation; Bicyclic compound; Peptidergic receptor; Ureas; Aromatic compound; Antagonist; R configuration; Pancreas; Chemical synthesis; Pancreatic disease; Rodentia; Pancreatitis; Oral administration; Gastric emptying; In vitro; In vivo; Vertebrata; Chemotherapy; Experimental disease; Mammalia; Treatment; Mouse; Animal; Digestive diseases; Affinity; Cholecystokinin; Brain (vertebrata)
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.48.1

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 panreatitis, we have prepared various 5-alkyl-9-methyl-1, 4-benzodiazepines. From the compounds prepared, 1-cyclo-hexyl-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 receprot 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.