Laguna R, Rodriguez-Liñares B, Cano E, Estevez I, Raviña E, Sotelo E
Laboratorio de Farmacología, Facultad de Farmacia, Universidad de Santiago de Compostela, Spain.
Chem Pharm Bull (Tokyo). 1997 Jul;45(7):1151-5. doi: 10.1248/cpb.45.1151.
Several 6-aryl-5-oxygenated substituted pyridazinones have been synthesized and evaluated in vitro for inhibition of platelet aggregation induced by adenosine 5'-diphosphate (ADP), thrombin and collagen. All the tested compounds (except 8 and 9) inhibited platelet aggregation in a dose-dependent manner. The IC50 of the most active substance, compound 2b, was around 60 microM against ADP and collagen as inducers. The inhibition of platelet aggregation caused by test compounds was dependent on the level of oxidation of the function at the 5-position, with the order of IC50 values being R-OH (2a, b, 5) < R-CHO (6, 7) < < R-COOH (8, 9). None of the tested compounds increased the intracellular levels of cAMP, indicating a lack of inhibitory activity on cAMP phosphodiesterase (PDE III) in intact cells. These results suggest that the group present at the 5 position of 6-aryl-5-substituted pyridazinones determines the platelet aggregation-inhibitory activity, and that a mechanism other than PDE inhibition is responsible for this effect.
已经合成了几种6-芳基-5-氧化取代哒嗪酮，并在体外评估了它们对由5'-二磷酸腺苷（ADP）、凝血酶和胶原蛋白诱导的血小板聚集的抑制作用。所有测试化合物（8和9除外）均以剂量依赖性方式抑制血小板聚集。最具活性的物质化合物2b对ADP和胶原蛋白诱导剂的IC50约为60μM。测试化合物引起的血小板聚集抑制作用取决于5位官能团的氧化程度，IC50值顺序为R-OH（2a、b、5）<R-CHO（6、7）<<R-COOH（8、9）。没有一种测试化合物能提高细胞内cAMP水平，这表明在完整细胞中对cAMP磷酸二酯酶（PDE III）缺乏抑制活性。这些结果表明，6-芳基-5-取代哒嗪酮5位上的基团决定了血小板聚集抑制活性，并且这种作用是由PDE抑制以外的机制引起的。
