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 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 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 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.
Highlights
Thromboembolic disorders, such as cerebral thrombosis, deep vein thrombosis, unstable angina, myocardial infarction, and thromboembolic stroke; are one of the major disorders that cause morbidities and mortalities worldwise [1]
We report the synthesis and evaluation of the thrombin, factor Xa (FXa), and U46619 inhibitory activities of non-amidino N2
1 The molecular weight of heparin used as positive control in our experiments is 3500
Summary
Thromboembolic disorders, such as cerebral thrombosis, deep vein thrombosis, unstable angina, myocardial infarction, and thromboembolic stroke; are one of the major disorders that cause morbidities and mortalities worldwise [1]. Hexadecasaccharide (e.g., SR123781) [11,12] is a synthetic heparin mimetic that inhibits both FXa and thrombin via antithrombin III that was advanced to phase I clinical trials This dual inhibitor demonstrated superior antithrombotic properties in three rat models of thrombosis following intravenous administration compared to selective factor Xa inhibitor, synthetic pentasaccharide fondaparinux (Arixtra®) [13]. 2-Aminobenzamides 21b–23b were synthesized from reduction of 2-nitrobenzamides 21a–23a with Fe and NH4Cl. The treatment of 21b–23b with thiophene-2-carbonyl chloride prepared the Scheme 3 illustrated the synthetic procedures of amidino N2-thiophenecarbonyl anthranilamide derivatives 21–23. The amidine group forms a bidentate salt bridge interaction with carboxylic acid of Asp189 in the S1 site of FXa. The high polar amidine-derived inhibitors demonstrated potent in vivo anticoagulant and antithrombotic activity. Compounds 11a–13a were refluxed with hydroxylamine hydrochloride and triethylamine in ethanol to provide the amidoxime derivatives 24b–26b to form amidinium chloride derivatives 24–26 via the catalytic hydrogenation of the O-acetyl amidoximes 24c–26c in 10% Pd/C and c-HCl at 60 psi, 45 ◦C for 12 h
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