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

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)A(2) mimic, with IC(50) values of 4.5 +/- 0.2, 3.9 +/- 0.1, and 9.3 +/- 0.5 microM, respectively. Moreover, NP-184 concentration-dependently suppressed TXA(2) formations caused by collagen and AA. In exploring effects of NP-184 on enzymes involved in TXA(2) synthesis, we found that NP-184 selectively inhibited TXA(2) synthase activity with an IC(50) value of 4.3 +/- 0.2 microM. Furthermore, NP-184 produced a right shift of the concentration-response curve of U46619, indicating a competitive antagonism on TXA(2)/prostaglandin H(2) 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.

• Authors: 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
• Journal: Naunyn-Schmiedeberg's archives of pharmacology (Naunyn Schmiedebergs Arch Pharmacol) Vol. 381 Issue 6 Pg. 495-505 (Jun 2010) ISSN: 1432-1912 [Electronic] Germany
• PMID: 20349046 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-(5-methyl-2-furyl)benzimidazole
• Anticoagulants
• Benzimidazoles
• Fibrinolytic Agents
• Platelet Aggregation Inhibitors

Topics

• Administration, Oral
• Animals
• Anticoagulants (administration & dosage, pharmacology)
• Benzimidazoles (administration & dosage, pharmacology)
• Blood Coagulation (drug effects)
• Dose-Response Relationship, Drug
• Fibrinolytic Agents (administration & dosage, pharmacology)
• Humans
• Inhibitory Concentration 50
• Male
• Mice
• Mice, Inbred ICR
• Platelet Aggregation (drug effects)
• Platelet Aggregation Inhibitors (administration & dosage, pharmacology)
• Venous Thrombosis (drug therapy)