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Int. J. Mol. Sci. 2017, 18(6), 1144; doi:10.3390/ijms18061144

Synthesis and Thrombin, Factor Xa and U46619 Inhibitory Effects of Non-Amidino and Amidino N2-Thiophenecarbonyl- and N2-Tosylanthranilamides

1
College of Pharmacy, Catholic University of Daegu, Hayang-ro 13-13, Hayang-eup, Gyeongsan-si, Gyeongbuk 712-702, Korea
2
College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics Based Creative Drug Research Team, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu 41566, Korea
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Academic Editor: Zdenek Wimmer
Received: 2 February 2017 / Revised: 6 April 2017 / Accepted: 25 April 2017 / Published: 31 May 2017
(This article belongs to the Section Bioactives and Nutraceuticals)
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Abstract

Thrombin (factor IIa) and factor Xa (FXa) are key enzymes at the junction of the intrinsic and extrinsic coagulation pathways and are the most attractive pharmacological targets for the development of novel anticoagulants. Twenty non-amidino N2-thiophencarbonyl- and N2-tosyl anthranilamides 120 and six amidino N2-thiophencarbonyl- and N2-tosylanthranilamides 2126 were synthesized to evaluate their activated partial thromboplastin time (aPTT) and prothrombin time (PT) using human plasma at a concentration of 30 µg/mL in vitro. As a result, compounds 5, 9, and 2123 were selected to study the further antithrombotic activity. The anticoagulant properties of 5, 9, and 2123 significantly exhibited a concentration-dependent prolongation of in vitro PT and aPTT, in vivo bleeding time, and ex vivo clotting time. These compounds concentration-dependently inhibited the activities of thrombin and FXa and inhibited the generation of thrombin and FXa in human endothelial cells. In addition, data showed that 5, 9, and 2123 significantly inhibited thrombin catalyzed fibrin polymerization and mouse platelet aggregation and inhibited platelet aggregation induced by U46619 in vitro and ex vivo. Among the derivatives evaluated, N-(3′-amidinophenyl)-2-((thiophen-2′′-yl)carbonylamino)benzamide (21) was the most active compound. View Full-Text
Keywords: N2-Arylcarbonyl/sulfonylanthranilamides; prothrombin time; activated partial thromboplastin time; Thrombin; Factor Xa; U46619 N2-Arylcarbonyl/sulfonylanthranilamides; prothrombin time; activated partial thromboplastin time; Thrombin; Factor Xa; U46619
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MDPI and ACS Style

Lee, S.H.; Lee, W.; Nguyen, T.; Um, I.S.; Bae, J.-S.; Ma, E. Synthesis and Thrombin, Factor Xa and U46619 Inhibitory Effects of Non-Amidino and Amidino N2-Thiophenecarbonyl- and N2-Tosylanthranilamides. Int. J. Mol. Sci. 2017, 18, 1144.

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