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.

Targeting Receptor Tyrosine Kinase VEGFR-2 in Hepatocellular Cancer: Rational Design, Synthesis and Biological Evaluation of 1,2-Disubstituted Benzimidazoles

“…Recently, 2-furylbenzimidazole scaffold has attracted much attention because of its promising angiokinase inhibitory activity [44][45][46]. For instance, NP184 (VII) was identified as a potent antiangiogenic agent [44,45]. Moreover, Pj-8 (VIII) significantly inhibited VEGFR-2 and suppressed tumor-induced angiogenesis in vivo ( Figure 3) [46].…”

Synthesis, Biological Evaluation, and Docking Studies of New 2‐Furylbenzimidazoles as Anti‐Angiogenic Agents: Part II

“…The discovery of new chemotherapeutic agents by blocking the VEGF‐induced angiogenesis has attracted much attention in the last few years . Since the 2‐furylbenzimidazole nucleus showed promising inhibition against VEGF‐induced angiogenesis in previous studies , we have synthesized several analogs of the 2‐furylbenzimidazole nucleuses 14 – 18 and measured their inhibition potency in vitro against human VEGF in human breast cancer cell line MCF‐7.…”

“…2‐(5‐Methyl‐2‐furyl)‐1 H ‐benzimidazole (NP‐184) 7 inhibited the angiogenic functions of HUVEC in vitro and reduced the angiogenesis rate in vivo in material plug assay model (Fig. ) . The structural modification of compound NP‐184 resulted in compound (PJ‐8) 8 , which extremely inhibited VEGF–VEGFR2 and suppressed the tumor‐induced angiogenesis in vivo .…”

Mechanisms of antiplatelet activity of nifedipine

“…Segments of the mesenteric microvessels were exposed on culture dishes for microscopic observation. The venules (30-40 mm) were selected for irradiation by using a halogen lamp to produce a microthrombus as described previously [19].…”