title: Studies on a novel, potent and orally effective cholecystokinin A antagonist, FK-480. Synthesis and structure-activity relationships of FK-480 and related compounds.
abstract: We prepared various novel tricyclic 1,4-benzodiazepine derivatives as cholecystokinin (CCK) A antagonists, which were evaluated preliminarily for inhibition of 125I-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)-alpha-methylbenzyl isocyanate. FK-480 is now undergoing clinical studies for the treatment of chronic pancreatitis.
authors: New Drug Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
authors: Y
authors: Y
authors: Satoh
authors: T
authors: T
authors: Matsuo
authors: H
authors: H
authors: Sogabe
authors: H
authors: H
authors: Itoh
authors: T
authors: T
authors: Tada
authors: T
authors: T
authors: Kinoshita
authors: K
authors: K
authors: Yoshida
authors: T
authors: T
authors: Takaya
mesh_terms: D000818:Animals; D001570:Benzodiazepinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D002766:Cholecystokinin / Q000037:antagonists & inhibitors*; D004341:Drug Evaluation; D004355:Drug Stability; D005746:Gastric Emptying / Q000187:drug effects; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism; D011355:Prodrugs / Q000737:chemistry; D051381:Rats; D012844:Sincalide / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D001570:Benzodiazepinones; D007211:Indoles; D011355:Prodrugs; C082966:FR 120480; D002766:Cholecystokinin; D012844:Sincalide