Novel Antagonists of Platelet-Activating Factor. 2. Synthesis and Structure-Activity Relationships of Potent and Long-Acting Heterofused Benzodiazepine and Diazepine Derivatives of 2-Methyl-1-phenylimidazopyridine

Article abstract of DOI:10.1021/jm00018a012

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-pyridine (4, UK-74,505) (ED50=0.26 mg/kg po).Compound 43 also possessed a longer duration of action than compound 4 in the conscious dog at one-fourth of the dose.The crystal structure of compound 43, established by X-ray diffraction, is reported.