Design, synthesis and antithrombotic evaluation of novel dabigatran etexilate analogs, a new series of non-peptides thrombin inhibitors.

Abstract

Thrombin is a serine protease that plays a key role in blood clotting, which makes it a promising target for the treatment of thrombotic diseases. Dabigatran is direct potent thrombin inhibitor. Based on bioisosteric and scaffold hopping principle, two dabigatran mimics (I-1 and II-1) in which the benzamidine moiety of dabigatran was replaced by a tricyclic fused scaffold were designed, synthesized and evaluated for their in vitro activities for inhibiting thrombin. The results reveal that compounds I-1 (IC50=9.20nM) and II-1 (IC50=7.48nM) are potent direct thrombin inhibitors and the activity is in the range of reference drug. On this basis, twenty-two ester and carbamate derivatives of I-1 or II-1 were prepared and evaluated for their anticoagulant activity. Prodrugs I-4a (IC50=0.73μM), I-4b (IC50=0.75μM), II-2a (IC50=1.44μM) and II-2b (IC50=0.91μM) display excellent effects of inhibiting thrombin induced-platelet aggregation. Moreover, compounds I-9 and II-4, which contain a cleavable moiety with anti-platelet activity, show the best anticoagulant efficacy among the tested compounds in the rat venous thrombosis model. The compounds which have better in vitro and in vivo activity were subjected to rat tail bleeding test, and the result demonstrates that compound I-9 is less likely to have bleeding risk than dabigatran etexilate.

• Authors: Dongxing Chen, Shaochi Wang, Xiaojuan Diao, Qihua Zhu, Huiliang Shen, Xueqing Han, Yiwei Wang, Guoqing Gong, Yungen Xu
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 23 Issue 23 Pg. 7405-16 (Dec 01 2015) ISSN: 1464-3391 [Electronic] England
• PMID: 26537784 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• Anticoagulants
• Platelet Aggregation Inhibitors
• Prodrugs
• Thrombin
• Dabigatran

Topics

• Animals
• Anticoagulants (chemical synthesis, chemistry, pharmacology)
• Dabigatran (analogs & derivatives, chemical synthesis, chemistry, pharmacology)
• Humans
• Male
• Mice
• Molecular Docking Simulation
• Platelet Aggregation Inhibitors (chemical synthesis, chemistry, pharmacology)
• Prodrugs (chemical synthesis, chemistry, pharmacology)
• Rabbits
• Rats
• Rats, Sprague-Dawley
• Thrombin (antagonists & inhibitors)