Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 381, Issue 6, pp 495–505

NP-184[2-(5-methyl-2-furyl) benzimidazole], a novel orally active antithrombotic agent with dual antiplatelet and anticoagulant activities

  • Heng-Lan Kuo
  • Jin-Cherng Lien
  • Ching-Hu Chung
  • Chien-Hsin Chang
  • Shyh-Chyi Lo
  • I-Chun Tsai
  • Hui-Chin Peng
  • Sheng-Chu Kuo
  • Tur-Fu Huang
Original Article

DOI: 10.1007/s00210-010-0505-x

Cite this article as:
Kuo, HL., Lien, JC., Chung, CH. et al. Naunyn-Schmied Arch Pharmacol (2010) 381: 495. doi:10.1007/s00210-010-0505-x

Abstract

The established antiplatelet and anticoagulant agents show beneficial effects in the treatment of thromboembolic diseases; however, these drugs still have considerable limitations. The effects of NP-184, a synthetic compound, on platelet functions, plasma coagulant activity, and mesenteric venule thrombosis in mice were investigated. NP-184 concentration-dependently inhibited the human platelet aggregation induced by collagen, arachidonic acid (AA), and U46619, a thromboxane (TX)A2 mimic, with IC50 values of 4.5 ± 0.2, 3.9 ± 0.1, and 9.3 ± 0.5 μM, respectively. Moreover, NP-184 concentration-dependently suppressed TXA2 formations caused by collagen and AA. In exploring effects of NP-184 on enzymes involved in TXA2 synthesis, we found that NP-184 selectively inhibited TXA2 synthase activity with an IC50 value of 4.3 ± 0.2 μM. Furthermore, NP-184 produced a right shift of the concentration–response curve of U46619, indicating a competitive antagonism on TXA2/prostaglandin H2 receptor. Intriguingly, NP-184 also caused a concentration-dependent prolongation of the activated partial thromboplastin time (aPTT) with no changes in the prothrombin and thrombin time, indicating that it selectively impairs the intrinsic coagulation pathway. Oral administration of NP-184 significantly inhibited thrombus formation of the irradiated mesenteric venules in fluorescein sodium-treated mice without affecting the bleeding time induced by tail transection. However, after oral administration, NP-184 inhibited the ex vivo mouse platelet aggregation triggered by collagen and U46619 and also prolonged aPTT. Taken together, the dual antiplatelet and anticoagulant activities of NP-184 may have therapeutic potential as an oral antithrombotic agent in the treatment of thromboembolic disorders.

Keywords

Antithrombotic TXA2 synthase TXA2/prostaglandin H2 receptor Platelets 

Abbreviations

AA

Arachidonic acid

TXA2

ThromboxaneA2

TP

TXA2/prostaglandin H2

U46619

9,11-Dideoxy-9α

11α

Methanoepoxy-prostaglandin F

TXAS

Thromboxane A2 synthase

PGH2

Prostaglandin H2

aPTT

Activated partial thromboplastin time

PT

Prothrombin time

TT

Thrombin time

TTO

Time to occlusion

DMSO

Dimethylsulfoxide

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Heng-Lan Kuo
    • 1
  • Jin-Cherng Lien
    • 2
  • Ching-Hu Chung
    • 3
  • Chien-Hsin Chang
    • 1
  • Shyh-Chyi Lo
    • 4
  • I-Chun Tsai
    • 1
  • Hui-Chin Peng
    • 1
  • Sheng-Chu Kuo
    • 2
  • Tur-Fu Huang
    • 1
  1. 1.Graduate Institute of Pharmacology, College of MedicineNational Taiwan UniversityTaipeiTaiwan
  2. 2.Graduate Institute of Pharmaceutical ChemistryChina Medical UniversityTaichungTaiwan
  3. 3.Institute of Pharmacology and ToxicologyTzu Chi UniversityHualienTaiwan
  4. 4.Department of Laboratory MedicineNational Taiwan University HospitalTaipeiTaiwan

Personalised recommendations