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Thromb Haemost 2016; 116(02): 285-299
DOI: 10.1160/TH15-12-0993
Cellular Haemostasis and Platelets
Schattauer GmbH

A novel thromboxane receptor antagonist, nstpbp5185, inhibits platelet aggregation and thrombus formation in animal models

Shiu-Wen Huang
1   Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan
,
Heng-Lan Kuo
1   Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan
,
Ming-Tsung Hsu
2   Genome and Systems Biology Degree Program, National Taiwan University and Academia Sinica, Taipei, Taiwan
,
Yufeng Jane Tseng
2   Genome and Systems Biology Degree Program, National Taiwan University and Academia Sinica, Taipei, Taiwan
3   Department of Computer Science and Information Engineering and ‡Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, No. 1 Sec. 4, Roosevelt Road, Taipei, Taiwan
4   Drug Research Center, National Taiwan University School of Medicine, No. 1, Sec. 1, Ren-ai Road, Taipei, Taiwan
,
Shu-Wha Lin
5   Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
6   Department of Laboratory Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
7   Center for Genomic Medicine, National Taiwan University, Taipei, Taiwan
,
Sheng-Chu Kuo
8   School of Pharmacy, China Medical University, Taichung, Taiwan
,
Hui-Chin Peng
1   Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan
,
Jin-Cherng Lien
8   School of Pharmacy, China Medical University, Taichung, Taiwan
,
Tur-Fu Huang
1   Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan
› Author Affiliations
Further Information

Publication History

Received: 28 December 2015

Accepted after major revision: 26 April 2016

Publication Date:
09 March 2018 (online)

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Summary

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 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 antithrombotic agent, acting through blockade of TXA2 receptor, may be efficacious for prevention or treatment of pathologic thrombosis.

Supplementary Material to this article is available online at www.thrombosis-online.com.

Keywords

Benzimidazole - mouse thrombotic model - thromboxane receptor antagonist

 

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