NOVEL ANTAGONISTS OF PLATELET-ACTIVATING-FACTOR .2. SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF POTENT AND LONG-ACTING HETEROFUSED [1,5]BENZODIAZEPINE AND [1,4]DIAZEPINE DERIVATIVES OF 2-METHYL-1-PHENYLIMIDAZO[4,5-C]PYRIDINE

The optimization of in vitro activity and oral potency and duration of action in vivo is described for three novel structural types of plate let-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 rea ctions of a variety of 2,3-diaminopyridine and 4,5-diaminopyrazole der ivatives with ethyl '-(2-methylimidazo[4,5-c]pyrid-1-yl)benzoylacetate (53). The presence of imine-enamine tautomerism was observed in certa in diazepine derivatives and is discussed. Structure-activity relation ships were evaluated where PAF antagonist activity was measured in vit ro by determining the concentration of compound (IC50) required to inh ibit PAF-induced aggregation of rabbit washed platelets and in vivo by determining the oral dose (ED(50)) which protected mice from a lethal injection of PAF. In addition, the duration of action in conscious do gs was measured by determining the oral dose of selected compounds req uired to inhibit completely PAF-induced whole blood aggregation ex-viv o. The most potent compound was ]-7-oxy-3-(3-pyridyl)pyrazolo[3,4-b][1 ,4]diazepine (43, UK-91,473) (IC50 = 2.4 nM, ED(50) = 0.01 mg/kg po), which was found to be significantly more potent in vivo (murine lethal ity) than the dihydropyridine PAF antagonist 4-(2-chlorophenyl)-1,4-di hydro-3-(ethoxy id-1-yl)phenyl]-5-[N-(2-pyridyl)carbamoyl]pyridine (4, UK-74,505) (ED(50) = 0.26 mg/kg po). Compound 43 also possessed a lon ger duration of action than compound 4 in the conscious dog at one-fou rth of the dose. The crystal structure of compound 43, established by X-ray diffraction, is reported.