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

Dongxing Chen; Shaochi Wang; Xiaojuan Diao; Qihua Zhu; Huiliang Shen; Xueqing Han; Yiwei Wang; Guoqing Gong; Yungen Xu

doi:10.1016/j.bmc.2015.10.036

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

Bioorg Med Chem. 2015 Dec 1;23(23):7405-16. doi: 10.1016/j.bmc.2015.10.036. Epub 2015 Oct 26.

Authors

Dongxing Chen¹, Shaochi Wang¹, Xiaojuan Diao², Qihua Zhu², Huiliang Shen³, Xueqing Han², Yiwei Wang², Guoqing Gong³, Yungen Xu⁴

Affiliations

¹ Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 21009, China.
² Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 21009, China; Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 21009, China.
³ Department of Pharmacology, China Pharmaceutical University, Nanjing 21009, China.
⁴ Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 21009, China; Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 21009, China. Electronic address: xu_yungen@hotmail.com.

PMID: 26537784
DOI: 10.1016/j.bmc.2015.10.036

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.

Keywords: Anticoagulant evaluation; Dabigatran etexilate analogs; Synthesis; Thrombin inhibitor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

Anticoagulants
Platelet Aggregation Inhibitors
Prodrugs
Thrombin
Dabigatran