Preprint Article Version 1 NOT YET PEER-REVIEWED

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

Version 1 : Received: 3 February 2017 / Approved: 3 February 2017 / Online: 3 February 2017 (18:55:26 CET)

How to cite: Lee, S.; Lee, W.; Ha, N.; Um, I.; Bae, J.; Ma, E. Synthesis and Thrombin, Factor Xa and U46619 Inhibitory Effects of Non-amidino and Amidino N2-Thiophenecarbonyl- and N2-Tosylanthranilamides. Preprints 2017, 2017020009 (doi: 10.20944/preprints201702.0009.v1). Lee, S.; Lee, W.; Ha, N.; Um, I.; Bae, J.; Ma, E. Synthesis and Thrombin, Factor Xa and U46619 Inhibitory Effects of Non-amidino and Amidino N2-Thiophenecarbonyl- and N2-Tosylanthranilamides. Preprints 2017, 2017020009 (doi: 10.20944/preprints201702.0009.v1).

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 1-20 and six amidino N2-thiophencarbonyl- and N2-tosylanthranilamides 21-26 were synthesized and evaluated prothrombin time (PT) and activated partial thromboplastin time (aPTT) using human plasma at concentration 30 μg/mL in vitro. From these results, compounds 5, 9, and 21-23 were selected to study the further antithrombotic activity. The anticoagulant properties of 5, 9, and 21-23 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 21-23 significantly inhibited thrombin catalyzed fibrin polymerization and mouse platelet aggregation and inhibited platelet aggregation induced U46619 in vitro and ex vivo. N-(3'-Amidinophenyl)-2-((thiophen-2''-yl)carbonyl amino)benzamide (21) was most active.

Subject Areas

N2-Arylcarbonyl/sulfonylanthranilamides; Prothrombin time; Activated partial thromboplastin time; Thrombin; Factor Xa; U46619

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