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

Shiu-Wen Huang; Heng-Lan Kuo; Ming-Tsung Hsu; Yufeng Jane Tseng; Shu-Wha Lin; Sheng-Chu Kuo; Hui-Chin Peng; Jin-Cherng Lien; Tur-Fu Huang

doi:10.1160/TH15-12-0993

Thrombosis and Haemostasis, Table of Contents

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

¹Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan

,

Heng-Lan Kuo

¹Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan

,

Ming-Tsung Hsu

²Genome and Systems Biology Degree Program, National Taiwan University and Academia Sinica, Taipei, Taiwan

,

Yufeng Jane Tseng

²Genome and Systems Biology Degree Program, National Taiwan University and Academia Sinica, Taipei, Taiwan

³Department 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

⁴Drug Research Center, National Taiwan University School of Medicine, No. 1, Sec. 1, Ren-ai Road, Taipei, Taiwan

,

Shu-Wha Lin

⁵Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan

⁶Department of Laboratory Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan

⁷Center for Genomic Medicine, National Taiwan University, Taipei, Taiwan

,

Sheng-Chu Kuo

⁸School of Pharmacy, China Medical University, Taichung, Taiwan

,

Hui-Chin Peng

¹Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan

,

Jin-Cherng Lien

⁸School of Pharmacy, China Medical University, Taichung, Taiwan

,

Tur-Fu Huang

¹Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan

› Author Affiliations

Abstract

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

Full Text

References

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