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

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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.

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Abbreviations

AA:

Arachidonic acid

TXA2 :

ThromboxaneA2

TP:

TXA2/prostaglandin H2

U46619:

9,11-Dideoxy-9α

11α:

Methanoepoxy-prostaglandin F2α

TXAS:

Thromboxane A2 synthase

PGH2 :

Prostaglandin H2

aPTT:

Activated partial thromboplastin time

PT:

Prothrombin time

TT:

Thrombin time

TTO:

Time to occlusion

DMSO:

Dimethylsulfoxide

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Acknowledgments

This work was supported by grants from the National Science Council (NSC 93-23-20-B-039-030, NSC 94-23-23-B-002-009, NSC 95-23-23-B-002-010, and CMU93-PC-02) and China Medical University (CMU93-PC-02) of Taiwan.

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Authors and Affiliations

  1. Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, No.1, Sec. 1, Jen-Ai Rd, Taipei, Taiwan

    Heng-Lan Kuo, Chien-Hsin Chang, I-Chun Tsai, Hui-Chin Peng & Tur-Fu Huang

  2. Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung, Taiwan

    Jin-Cherng Lien & Sheng-Chu Kuo

  3. Institute of Pharmacology and Toxicology, Tzu Chi University, Hualien, Taiwan

    Ching-Hu Chung

  4. Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan

    Shyh-Chyi Lo

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  1. Heng-Lan Kuo
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  9. Tur-Fu Huang
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Correspondence to Tur-Fu Huang.

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Kuo, HL., Lien, JC., Chung, CH. et al. NP-184[2-(5-methyl-2-furyl) benzimidazole], a novel orally active antithrombotic agent with dual antiplatelet and anticoagulant activities. Naunyn-Schmied Arch Pharmacol 381, 495–505 (2010). https://doi.org/10.1007/s00210-010-0505-x

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