A novel thromboxane receptor antagonist, nstpbp5185, inhibits platelet aggregation and thrombus formation in animal models
Journal
Thrombosis and Haemostasis
Journal Volume
116
Journal Issue
2
Pages
285_299
Date Issued
2016
Author(s)
Huang S.-W.
Kuo H.-L.
Hsu M.-T.
Kuo S.-C.
Peng H.-C.
Lien J.-C.
Abstract
A novel benzimidazole derivative, nstpbp5185, was discovered through in vitro and in vivo evaluations for antiplatelet activity. Thro-maboxane receptor (TP) is important in vascular physiology, haemostasis and pathophysiological thrombosis. Nstpbp5185 concentration-dependently inhibited human platelet aggregation caused by collagen, arachidonic acid and U46619. Nstpbp5185 caused a right-shift of the concentration-response curve of U46619 and competitively inhibited the binding of3H-SQ-29548 to TP receptor expressed on HEK-293 cells, with an IC50 of 0.1 uM, indicating that nstpbp5185 is a TP antagonist. In murine thrombosis models, nstpbp5185 significantly prolonged the latent period in triggering platelet plug formation in mesenteric and FeCl3-induced thrombi formation, and increased the survival rate in pulmonary embolism model with less bleeding than aspirin. This study suggests nstpbp5185, an orally selective antithrombotic agent, acting through blockade of TXA2 receptor, may be efficacious for prevention or treatment of pathologic thrombosis. ? Schattauer 2016.
SDGs
Other Subjects
adrenalin; collagen; fluorescein sodium; nstpbp 5185; PADGEM protein; pentobarbital; thrombocyte antigen; thromboxane A2; thromboxane receptor; thromboxane receptor blocking agent; unclassified drug; 1-benzyl-2-(5-methyl-2-furyl)benzimidazole; 15 hydroxy 11alpha,9alpha epoxymethanoprosta 5,13 dienoic acid; acetylsalicylic acid; arachidonic acid; benzimidazole derivative; calcium; collagen; PADGEM protein; thromboxane A2; thromboxane A2 receptor; animal experiment; animal model; animal tissue; Article; bleeding time; blood clotting; chemoluminescence; flow cytometry; fluorescence; histology; immunoblotting; immunoreactivity; male; molecular docking; mouse; nonhuman; priority journal; thrombocyte aggregation; thrombocyte rich plasma; thrombosis; animal; antagonists and inhibitors; blood; drug effects; human; in vitro study; Institute for Cancer Research mouse; lung embolism; metabolism; microvasculature; thrombocyte; thrombocyte aggregation; thrombosis; 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Arachidonic Acid; Aspirin; Benzimidazoles; Blood Platelets; Calcium; Collagen; Humans; In Vitro Techniques; Male; Mice; Mice, Inbred ICR; Microvessels; P-Selectin; Platelet Aggregation; Pulmonary Embolism; Receptors, Thromboxane A2, Prostaglandin H2; Thrombosis; Thromboxane A2
Type
journal article