Fray M J, Bull D J, Cooper K, Parry M J, Stefaniak M H
Department of Discovery Biology, Pfizer Central Research, Sandwich, Kent, UK.
J Med Chem. 1995 Sep 1;38(18):3524-35. doi: 10.1021/jm00018a012.
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.
本文描述了三种新型结构类型的血小板活化因子（PAF）拮抗剂在体外活性、口服效价及体内作用持续时间方面的优化情况：[1,5]苯并二氮杂卓类化合物5 - 12，其上稠合了各种其他杂环；吡啶并[2,3 - b][1,4]二氮杂卓酮类化合物13 - 26；以及吡唑并[3,4 - b][1,4]二氮杂卓酮类化合物27 - 46。化合物5 - 12通过对[1,5]苯并二氮杂卓 - 2 - 硫酮47和48进行衍生化制备，13 - 46则通过多种2,3 - 二氨基吡啶和4,5 - 二氨基吡唑衍生物与4' - (2 - 甲基咪唑并[4,5 - c]吡啶 - 1 - 基)苯甲酰乙酸乙酯（53）的环缩合反应制备。在某些二氮杂卓衍生物中观察到了亚胺 - 烯胺互变异构现象并进行了讨论。通过测定抑制PAF诱导的兔洗涤血小板聚集所需的化合物浓度（IC50）来体外测定PAF拮抗剂活性，并通过测定保护小鼠免受致死剂量PAF注射的口服剂量（ED50）来体内评估构效关系。此外，通过测定抑制离体PAF诱导的全血聚集所需的选定化合物的口服剂量，来测定清醒犬体内的作用持续时间。最有效的化合物是1,6,7,8 - 四氢 - 1,8 - 二甲基 - 5 - [4 - (2 - 甲基咪唑并[4,5 - c]吡啶 - 1 - 基)phenyl] - 7 - 氧代 - 3 - (3 - 吡啶基)吡唑并[3,4 - b][1,4]二氮杂卓（43，UK - 91,473）（IC50 = 2.4 nM，ED50 = 0.01 mg/kg口服），发现其在体内（小鼠致死性）比二氢吡啶PAF拮抗剂4 - (2 - 氯苯基) - 1,4 - 二氢 - 3 - (乙氧羰基) - 6 - 甲基 - 4 - [(2 - 甲基咪唑并[4,5 - c]吡啶 - 1 - 基)phenyl] - 5 - [N - (2 - 吡啶基)氨基甲酰基]吡啶（4，UK - 74,505）（ED50 = 0.26 mg/kg口服）效力显著更强。在清醒犬中，化合物43在四分之一剂量时的作用持续时间也比化合物4长。报道了通过X射线衍射确定的化合物43的晶体结构。
