Synthesis, Pharmacological Characterization, and Docking Analysis of a Novel Family of Diarylisoxazoles as Highly Selective Cyclooxygenase-1 (COX-1) Inhibitors

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• 作者：Paola Vitale ; Stefania Tacconelli ; Maria Grazia Perrone ; Paola Malerba ; Laura Simone ; Antonio Scilimati ; Antonio Lavecchia ; Melania Dovizio ; Emanuela Marcantoni ; Annalisa Bruno ; Paola Patrignani
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：June 13, 2013
• 年：2013
• 卷：56
• 期：11
• 页码：4277-4299
• 全文大小：958K
• 年卷期：v.56,no.11(June 13, 2013)
• ISSN：1520-4804

文摘

3-(5-Chlorofuran-2-yl)-5-methyl-4-phenylisoxazole (P6), a known selective cyclooxygenase-1 (COX-1) inhibitor, was used to design a new series of 3,4-diarylisoxazoles in order to improve its biochemical COX-1 selectivity and antiplatelet efficacy. Structure鈥揳ctivity relationships were studied using human whole blood assays for COX-1 and COX-2 inhibition in vitro, and results showed that the simultaneous presence of 5-methyl (or -CF₃), 4-phenyl, and 5-chloro(-bromo or -methyl)furan-2-yl groups on the isoxazole core was essential for their selectivity toward COX-1. 3g, 3s, 3d were potent and selective COX-1 inhibitors that affected platelet aggregation in vitro through the inhibition of COX-1-dependent thromboxane (TX) A₂. Moreover, we characterized their kinetics of COX-1 inhibition. 3g, 3s, and 3d were more potent inhibitors of platelet COX-1 and aggregation than P6 (named 6) for their tighter binding to the enzyme. The pharmacological results were supported by docking simulations. The oral administration of 3d to mice translated into preferential inhibition of platelet-derived TXA₂ over protective vascular-derived prostacyclin (PGI₂).