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

Publisher Website
Google Scholar
Abstract
We prepared various novel tricyclic 1, 4-benzodiazepine derivatives as cholecystokinin (CCK) A antagonists, which were evaluated preliminarily for inhibition of 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, R1=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.

This publication has 0 references indexed in Scilit: