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.

The medicinal panorama of benzimidazoles and their scaffolds as anticancer and antithrombotic agents: A review

“…To discover the innovative DTIs, an array of dabigatran etexilate scaffolds (365a-g, 366a-g) were synthesized by substituting the benzimidazole segment in dabigatran with 1,2,3,4tetrahydrobenzo [4,5]imidazo[1,2-a]pyrazine by Wang et al [117] in the year 2015 (Scheme 45). Apart from this, a bifunctional prodrug 366h was developed by replacing the ethyl group in molecule 365e…”

Direct Access to Highly Functionalised Benzimidazoles and Benzoxazoles from a Common Precursor

“…Benzimidazole is a well-known heterocyclic ring commonly encountered in medicinal chemistry. 3 Its functionalisation around 1-, 2-, 5-, and/or 6-positions provides a wide range of molecules of biological interest as anticancer (Bendamustine), 4 anticoagulant (Dabigatran etexilate), 5 antiulcer (Omeprazole), 6 antihypertensive, antiviral, anthelmintic, among others. All these outstanding achievements strongly reflect the plethoric pharmacological activities of benzimidazole framework (Figure 1).…”