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).
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blood Platelets / drug effects
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Blood Platelets / metabolism
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Cell Line
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Cyclooxygenase 1 / metabolism*
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Cyclooxygenase 2 / metabolism
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Cyclooxygenase 2 Inhibitors / chemical synthesis
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Cyclooxygenase 2 Inhibitors / chemistry
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Cyclooxygenase 2 Inhibitors / pharmacology
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Cyclooxygenase Inhibitors / chemical synthesis*
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Cyclooxygenase Inhibitors / chemistry
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Cyclooxygenase Inhibitors / pharmacology
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Epoprostenol / metabolism
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Female
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Fibrinolytic Agents / chemical synthesis*
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Fibrinolytic Agents / chemistry
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Fibrinolytic Agents / pharmacology
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Furans / chemical synthesis*
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Furans / chemistry
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Furans / pharmacology
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Humans
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Isoxazoles / chemical synthesis*
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Isoxazoles / chemistry
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Isoxazoles / pharmacology
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Mice
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Mice, Inbred C57BL
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Molecular Docking Simulation
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Platelet Aggregation / drug effects
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Platelet Aggregation Inhibitors / chemical synthesis*
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Platelet Aggregation Inhibitors / chemistry
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Platelet Aggregation Inhibitors / pharmacology
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Platelet-Rich Plasma
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Structure-Activity Relationship
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Thromboxane A2 / antagonists & inhibitors
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Thromboxane A2 / biosynthesis
Substances
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3-(5-chlorofuran-2-yl)-4-phenyl-5-(trifluoromethyl)isoxazole
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Cyclooxygenase 2 Inhibitors
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Cyclooxygenase Inhibitors
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Fibrinolytic Agents
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Furans
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Isoxazoles
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Platelet Aggregation Inhibitors
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Thromboxane A2
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Epoprostenol
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Cyclooxygenase 1
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Cyclooxygenase 2