title: Synthesis, pharmacological characterization, and docking analysis of a novel family of diarylisoxazoles as highly selective cyclooxygenase-1 (COX-1) inhibitors.
abstract: 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-activity 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).
authors: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari A. Moro, Via Orabona 4, 70125 Bari, Italy.
authors: Paola
authors: P
authors: Vitale
authors: Stefania
authors: S
authors: Tacconelli
authors: Maria Grazia
authors: MG
authors: Perrone
authors: Paola
authors: P
authors: Malerba
authors: Laura
authors: L
authors: Simone
authors: Antonio
authors: A
authors: Scilimati
authors: Antonio
authors: A
authors: Lavecchia
authors: Melania
authors: M
authors: Dovizio
authors: Emanuela
authors: E
authors: Marcantoni
authors: Annalisa
authors: A
authors: Bruno
authors: Paola
authors: P
authors: Patrignani
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011464:Epoprostenol / Q000378:metabolism; D005260:Female; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D062105:Molecular Docking Simulation; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D053657:Platelet-Rich Plasma; D013329:Structure-Activity Relationship; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis
chemical_list: C582911:3-(5-chlorofuran-2-yl)-4-phenyl-5-(trifluoromethyl)isoxazole; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D005343:Fibrinolytic Agents; D005663:Furans; D007555:Isoxazoles; D010975:Platelet Aggregation Inhibitors; D013928:Thromboxane A2; D011464:Epoprostenol; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2