Studies on a Novel, Potent and Orally Effective Cholecystokinin A Antagonist, FK-480. Synthesis and Structure-Activity Relationships of FK-480 and Related Compounds

概要

論文の詳細を見る
We prepared various novel tricyclic 1,4-benzodiazepine derivatives as cholecystokinin (CCK) A antagonists, which were evaluated preliminarily for inhibition of <125>I-CCK-8 binding to rat pancreatic membranes in vitro and inhibiting effect on CCK-8-induced inhibition of charcoal meal gastric emptying in mice. On the basis of structure-activity relationship (SAR) studies, as well as the stability and availability of the starting materials of those compounds, (S)-N-[1-(2-fluorophenyl)-3,4,6,7-tetrahydro-4-oxo-pyrrolo[3,2,1-jk][1,4]benzodiazepin-3-yl]-1H-indole-2-carboxamide (9f, FK-480) was selected as a candidate compound for further evaluation. The absolute configuration of the precursor of FK-480,(3S)-amino-1,4-benzodiazepine derivative ((S)-8a, R^1=F) was determined by an X-ray crystallographic study of its ureido derivative with (S)-α-methylbenzyl isocyanate.FK-480 is now undergoing clinical studies for the treatment of chronic pancreatitis.
社団法人日本薬学会の論文
1994-10-15