Costas Tamara, Costas-Lago María Carmen, Vila Noemí, Besada Pedro, Cano Ernesto, Terán Carmen
Departamento de Química Orgánica, Universidade de Vigo, 36310 Vigo, Spain; Instituto de Investigación Biomédica (IBI), Universidade de Vigo, 36310 Vigo, Spain.
Departamento de Farmacoloxía, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain.
Eur J Med Chem. 2015 Apr 13;94:113-22. doi: 10.1016/j.ejmech.2015.02.061. Epub 2015 Mar 3.
New series of pyridazinone derivatives (4, 5 and 6) were synthesized in good yields following a synthetic strategy based on singlet oxygen oxidation of alkyl furans, in which a suitable β(α)-substituted γ-hydroxybutenolide (10 or 11) or a bicyclic lactone (12 or 13) was the key intermediate. The synthesized compounds were tested in vitro as antiplatelet agents and some of them (compounds 4b, 4d and 5b) exhibited potent inhibitory effects on collagen-induced platelet aggregation with IC50 values in the low μM range. Studies performed with the most active compound of these series (4b) demonstrated its lack of activity as inhibitor of platelet aggregation induced by other agonists as thrombin, ionomycin or U-46619 suggesting a selective action on the biochemical mechanisms triggered by collagen in the platelets.
基于烷基呋喃的单线态氧氧化合成策略，以合适的β(α)-取代γ-羟基丁烯内酯（10或11）或双环内酯（12或13）为关键中间体，高收率地合成了一系列新的哒嗪酮衍生物（4、5和6）。所合成的化合物作为抗血小板药物进行了体外测试，其中一些化合物（化合物4b、4d和5b）对胶原诱导的血小板聚集表现出强效抑制作用，IC50值在低 microM 范围内。对该系列中活性最高的化合物（4b）进行的研究表明，它作为凝血酶、离子霉素或U-46619等其他激动剂诱导的血小板聚集抑制剂没有活性，这表明它对血小板中胶原触发的生化机制具有选择性作用。
