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 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 as 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- [N-(2-pyridyl)carbamoyl]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.
Fray
M J
MJ
Department of Discovery Biology, Pfizer Central Research, Sandwich, Kent, UK.
Bull
D J
DJ
Cooper
K
K
Parry
M J
MJ
Stefaniak
M H
MH
D000818:Animals; D001381:Azepines / Q000737:chemistry / Q000494:pharmacology*; D001554:Benzene / Q000737:chemistry; D001569:Benzodiazepines / Q000737:chemistry / Q000494:pharmacology*; D004095:Dihydropyridines / Q000737:chemistry / Q000494:pharmacology*; D004285:Dogs; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D051379:Mice; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011720:Pyrazoles / Q000737:chemistry; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
C095432:2-methyl-1-phenylimidazo(4,5-c)pyridine; D001381:Azepines; D004095:Dihydropyridines; D007093:Imidazoles; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D001569:Benzodiazepines; C031280:pyrazole; D001554:Benzene