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

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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 ID_<50> 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.
公益社団法人日本薬学会の論文
2000-01-01