Design, Synthesis, and Biological Evaluation of Dabigatran Etexilate Mimics, a Novel Class of Thrombin Inhibitors.

Abstract

Human α-thrombin is a particularly promising target for anticoagulant therapy, and identification of oral small-molecular inhibitors of thrombin remains a research focus. On the basis of the X-ray crystal structure of human α-thrombin and its inhibitor dabigatran, we designed and synthesized a series of dabigatran etexilate mimics containing a novel tricyclic fused scaffold. The biological evaluations reveal that all of the compounds possess moderate activity of antiplatelet aggregation induced by thrombin in vitro. Moreover, compound I-8, which contains 2-hydroxymethyl-3,5,6-trimethylpyrazine (HTMP), a cleavable moiety with antiplatelet activity, shows the best anticoagulant effect among the tested compounds in vivo. Those synthesized compounds that have better in vitro activity were subjected to bleeding complication tests, and the results demonstrate that the novel compounds are less likely to have bleeding risk than dabigatran etexilate.

• Authors: Shaochi Wang, Peng Dai, Yungen Xu, Qiufang Chen, Qihua Zhu, Guoqing Gong
• Journal: Archiv der Pharmazie (Arch Pharm (Weinheim)) Vol. 348 Issue 8 Pg. 595-605 (Aug 2015) ISSN: 1521-4184 [Electronic] Germany
• PMID: 26120827 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Antithrombins
• Ligands
• Thrombin
• Dabigatran

Topics

• Animals
• Antithrombins (chemical synthesis, metabolism, pharmacology, toxicity)
• Binding Sites
• Crystallography, X-Ray
• Dabigatran (analogs & derivatives, chemical synthesis, metabolism, pharmacology, toxicity)
• Disease Models, Animal
• Drug Design
• Hemorrhage (chemically induced)
• Humans
• Ligands
• Mice
• Molecular Docking Simulation
• Molecular Mimicry
• Platelet Aggregation (drug effects)
• Protein Binding
• Protein Conformation
• Rabbits
• Rats
• Rats, Sprague-Dawley
• Risk Assessment
• Structure-Activity Relationship
• Thrombin (antagonists & inhibitors, chemistry, metabolism)
• Venous Thrombosis (blood, prevention & control)