Design, Synthesis, and Biological Evaluation of Dabigatran Etexilate Mimics, a Novel Class of Thrombin Inhibitors. Issue 8 (29th June 2015)

• Record Type: Journal Article
• Authors: Wang, Shaochi; Dai, Peng; Xu, Yungen; Chen, Qiufang; Zhu, Qihua; Gong, Guoqing
• Is Part Of: Archiv der Pharmazie. Volume 348:Issue 8(2015:Aug.)
• Page Start: 595
• Page End: 605
• Publication Date: 2015-06-29
• Subjects: Pharmaceutical chemistry -- Periodicals; Pharmacology -- Periodicals; 615.19
• DOI: 10.1002/ardp.201500101
• Languages: English
• ISSNs: 0365-6233

Abstract

<abstract abstract-type="main" xml:lang="en"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="ardp201500101-sec-0001" sec-type="section"> <p>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 <italic>in vitro</italic>. Moreover, compound <bold>I‐8</bold>, which contains 2‐hydroxymethyl‐3, 5, 6‐trimethylpyrazine (HTMP), a cleavable moiety with antiplatelet activity, shows the best anticoagulant effect among the tested compounds <italic>in vivo</italic>. Those synthesized compounds that have better <italic>in vitro</italic> 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.</p> </sec> </abstract>