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
Mj. Fray et al., 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, Journal of medicinal chemistry, 38(18), 1995, pp. 3524-3535
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.