Journal of Medicinal Chemistry p. 3524 - 3535 (1995)
Update date:2022-08-04
Topics:
Fray, M. Jonathan
Bull, David J.
Cooper, Kelvin
Parry, M. John
Stefaniak, Mark H.
The optimization of in vitro activty and oral potency and duration of action in vivo is described for three novel structural types of platelet-activating factor (PAF) antagonist: <1,5>benzodiazepines 5-12 onto which a variety of other heterocyclic rings were fused, pyrido<2,3-b><1,4>diazepinones 13-26, and pyrazolo<3,4-b><1,4>diazepinones 27-46.Compounds 5-12 were prepared by elaboration of the <1,5>benzodiazepine-2-thiones 47 and 48, and 13-46 were prepared by cyclocondensation reactions of a variety of 2,3-diaminopyridine and 4,5-diaminopyrazole derivatives with ethyl 4'-(2-methylimidazo<4,5-c>pyrid-1-yl)benzoylacetate (53).The presence of imine-enamine tautomerism was observed in certain diazepine derivatives and is discussed.Structure-activity relationships were evaluated where PAF antagonist activity was measured in vitro by determining the concentration of compound (IC50) required to inhibit PAF-induced aggregation of rabbit washed platelets and in vivo by determining the oral dose (ED50) which protected mice from a lethal injection of PAF.In addition, the duration of action in conscious dogs was measured by determining the oral dose of selected compounds required to inhibit completely PAF-induced whole blood aggregation ex vivo.The most potent compound was 1,6,7,8-tetrahydro-1,8-dimethyl-5-<4-(2-methylimidazo<4,5-c>pyrid-1-yl)phenyl>-7-oxo-3-(3-pyridyl)pyrazolo<3,4-b><1,4>diazepine (43, UK-91,473) (IC50=2.4 nM, ED50=0.01 mg/kg po), which was found to be significantly more potent in vivo (murine lethality) than the dihydropyridine PAF antagonist 4-(2-chlorophenyl)-1,4-dihydro-3-(ethoxycarbonyl)-6-methyl-4-<(2-methylimidazo<4,5-c>pyrid-1-yl)phenyl>-5-
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