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Development of Benzimidazole Derivatives as Novel Anti-platelet Drugs

[ Vol. 18 , Issue. 7 ]

Author(s):

Wei-Cheng Yao, Lan-Ting Yuan, Wen-Bin Yang, Chih-Hsuan Hsia, Li-Ting Huang, Tzu-Yin Lee, Joen-Rong Sheu, Wan-Jung Lu, Thanasekaran Jayakumar and Ray-Jade Chen   Pages 594 - 605 ( 12 )

Abstract:


Background: Benzimidazoles are privileged biomolecules which form an integral part of vitamin B12 and have been attracting numerous researchers all over the world to assess their potential therapeutic significance.

Objectives: The comparative in vitro antiplatelet activity of newly synthesized benzimidazole derivatives, M3BIM, C2BIM, and L2BIM in thrombin, adenosine diphosphate (ADP) and epinephrineinduced washed human platelets was investigated.

Method: Reversed-phase silica gel column chromatography, Aggregometry, Flow cytometry and Immunoblotting were used in this study.

Results: M3BIM exhibited a concentration (25-100 µM) dependent inhibitory effect on platelet aggregation induced by thrombin (0.01 U/mL) in washed human platelets and by epinephrine (10 µM) only at a maximum concentration of 500 µM in platelet-rich plasma (PRP); however, C2BIM and L2BIM had no response even at 500 µM against thrombin and 1mM against epinephrine-induced platelet aggregation. Moreover, all these three compounds were not inhibited platelet aggregation induced by ADP (20 µM). Additionally, these compounds showed no effects in thrombin-induced P-selectin expression and αIIbβ3 activation, as evidenced by flow cytometry and clot reaction assays, respectively. Besides, M3BIM (100 µM) significantly abolished thrombin-induced Akt and mitogen-activated protein kinases (MAPKs) phosphorylation; whereas 200 µM C2BIM and L2BIM were not effective on these proteins.

Conclusion: This study affords confirmation for the inhibitory effect of M3BIM in a low dose thrombin and epinephrine-induced platelet aggregation in vitro compared to other imidazole derivatives, C2BIM and L2BIM. These outcomes may recommend that M3BIM can be appraised as a prospective benzeimidazole compound for the treatment of thrombin -induced platelet defect and its related diseases.

Keywords:

Platelets, benzimidazole, thrombin, ADP, epinephrine, P-selectin, clot retraction, MAPKs.

Affiliation:

Department of Pharmacology, Graduate Institute of Medical Sciences and School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Department of Pharmacology, Graduate Institute of Medical Sciences and School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Genomics Research Center, Academia Sinica, Taipei 115, Department of Pharmacology, Graduate Institute of Medical Sciences and School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Department of Pharmacology, Graduate Institute of Medical Sciences and School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Department of Pharmacology, Graduate Institute of Medical Sciences and School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Department of Pharmacology, Graduate Institute of Medical Sciences and School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Department of Pharmacology, Graduate Institute of Medical Sciences and School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, 250 Wu-Hsing St., Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, 252 Wu-Hsing St., Division of General Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei 110

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