da Silveira I A, Paulo L G, de Miranda A L, Rocha S O, Freitas A C, Barreiro E J
Departamento de Farmacologia Básica e Clinica, Universidade Federal do Rio de Janeiro, Brasil.
J Pharm Pharmacol. 1993 Jul;45(7):646-9. doi: 10.1111/j.2042-7158.1993.tb05670.x.
A series of 5-pyrazolylhydrazone derivatives was designed to be mixed hybrid isosteres of both BW755C and CBS-1108, which belong to the class of dual cyclo-oxygenase and 5-lipoxygenase inhibitors. Some derivatives of this series inhibit the in-vitro platelet aggregation of citrated platelet-rich rabbit plasma induced by ADP (5 microM), collagen (5 micrograms mL-1) and arachidonic acid (100 microM). The structure-activity relationships of this class of compounds were determined from these results. When ADP is used as the aggregation inducer, the presence of free oxygenated substituents at the p-position in the phenyl subunit of the hydrazone moiety favours inhibitory activity; p-methoxyformylbenzene-5-(1-phenyl-3-methyl-4-nitropyrazolyl )hydrazone (100 microM), which has a methoxy group at this position was the most active with 62.8% inhibition of aggregation. In contrast, substitution in the aryl ring does not affect the aggregation induced by collagen, whereas the non-substituted compound, formylbenzene-5-(1-phenyl-3-methyl-4-nitropyrazolyl)hydra zon e, showed similar activity to those of substituted derivatives. In the arachidonic acid assays, the presence of an aryl ring linked to the hydrazone moiety, with an adequate electronic density at the ring due to the nature of its substituents, is an important structural requirement for inhibitory activity.
设计了一系列5-吡唑基腙衍生物，使其成为BW755C和CBS-1108的混合杂化电子等排体，这两种化合物属于双环氧化酶和5-脂氧合酶抑制剂类别。该系列的一些衍生物可抑制由ADP（5微摩尔）、胶原（5微克/毫升）和花生四烯酸（100微摩尔）诱导的枸橼酸化富含血小板兔血浆的体外血小板聚集。根据这些结果确定了这类化合物的构效关系。当使用ADP作为聚集诱导剂时，腙部分苯基亚基中对位存在游离的含氧取代基有利于抑制活性；在此位置有甲氧基的对甲氧基甲酰基苯-5-(1-苯基-3-甲基-4-硝基吡唑基)腙（100微摩尔）活性最高，聚集抑制率为62.8%。相比之下，芳环上的取代对胶原诱导的聚集没有影响，而未取代的化合物，甲酰基苯-5-(1-苯基-3-甲基-4-硝基吡唑基)腙，与取代衍生物表现出相似的活性。在花生四烯酸试验中，与腙部分相连的芳环由于其取代基的性质在环上具有适当的电子密度，是抑制活性的重要结构要求。
