title: A novel thromboxane receptor antagonist, nstpbp5185, inhibits platelet aggregation and thrombus formation in animal models.
abstract: A novel benzimidazole derivative, nstpbp5185, was discovered through in vitro and in vivo evaluations for antiplatelet activity. Thromaboxane 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 of 3H-SQ-29548 to TP receptor expressed on HEK-293 cells, with an IC50 of 0.1 µM, 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 anti-thrombotic agent, acting through blockade of TXA2 receptor, may be efficacious for prevention or treatment of pathologic thrombosis.
authors.forename: Shiu-Wen
authors.initials: SW
authors.lastname: Huang
authors.forename: Heng-Lan
authors.initials: HL
authors.lastname: Kuo
authors.forename: Ming-Tsung
authors.initials: MT
authors.lastname: Hsu
authors.forename: Yufeng Jane
authors.initials: YJ
authors.lastname: Tseng
authors.forename: Shu-Wha
authors.initials: SW
authors.lastname: Lin
authors.forename: Sheng-Chu
authors.initials: SC
authors.lastname: Kuo
authors.forename: Hui-Chin
authors.initials: HC
authors.lastname: Peng
authors.affiliation: Dr. Jin-Cherng Lien, School of Pharmacy, China Medical University, No.91 Hsueh-Shih Road, Taichung 40402, Taiwan, Tel.: +886 4 22053366 ext 5609, E-mail: jclien@mail.cmu.edu.tw.
authors.forename: Jin-Cherng
authors.initials: JC
authors.lastname: Lien
authors.affiliation: Dr. Tur-Fu Huang, Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, No.1, Section 1, Jen Ai Road, Taipei, Taiwan, Tel.: + 886 2 23123456 ext 88332, Fax: + 886 2 23417930, E-mail: turfu@ntu.edu.tw.
authors.forename: Tur-Fu
authors.initials: TF
authors.lastname: Huang
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000097:blood; D003094:Collagen / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D055806:Microvessels / Q000187:drug effects; D019007:P-Selectin / Q000097:blood; D010974:Platelet Aggregation / Q000187:drug effects*; D011655:Pulmonary Embolism / Q000517:prevention & control; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000037:antagonists & inhibitors*; D013927:Thrombosis / Q000517:prevention & control*; D013928:Thromboxane A2 / Q000097:blood
chemical_list: C000625903:1-benzyl-2-(5-methyl-2-furyl)benzimidazole; D001562:Benzimidazoles; D019007:P-Selectin; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D016718:Arachidonic Acid; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D003094:Collagen; D001241:Aspirin; D002118:Calcium
keywords: Benzimidazole; mouse thrombotic model; thromboxane receptor antagonist