Design,Synthesis And Anticoagulant Activity Research Of Dabigatran Analogues With Aromatic Ring Substituted Pyridine Ring

Thromboembolic disease is a high mortality and morbidity.Thrombin plays an important role in the process of thrombosis.Therefore,one way to treat thrombotic disease is to inhibit the activity of thrombin.Dabigatran etexilate on the market in 2008 is a direct thrombin inhibitor which is potent,reversible and nonpeptidic.The orally administered prodrug is hydrolized in vivo by esterases into the active form,dabigatran,which directly inhibits the thrombin activity.Dabigatran etexilate has good anticoagulation effect.But this new anticoagulant has several disadvantages,including low oral bioavailability and probability of haemorrhage when used in large dose.Therefore,development of more secure,efficient new anticoagulant drugs is still one of the hot spots of anti thrombotic therapy.Because of the small radius and high electric negative characteristics of the fluorine atom,the introduction of fluorine atom can significantly change the physical and chemical properties of the drug molecules.Fluorine substitution is commonly used in contemporary medicinal chemistry to improve metabolic stability,bioavailability and protein-ligand interactions.Moreover,fluorine introduction also facilitates improved selectivity for target organs and enhances drug efficacy.Therefore,the introduction of fluorine to dabigatran is an important strategy for discovering the novel candidate compounds.In the paper,we combine the benefits of dabigatran and fluorine atoms during treatment.Through the technology of computer-aided drug design,15 dabigatran analogues with aromatic ring substituted pyridine ring which have not been reported were designed.These analogues were then synthesized through a series of chemical reactions.All compounds were preliminarily screened at 1?g/mL for inhibitory activity against thrombin.In accordance with the results of the preliminary screening,11 compounds were evaluated in vitro.These compounds showed potent anticoagulant activities against thrombin.Compounds 14k(IC50=0.84 nM)and 14m(IC50= 1.18 nM)showed higher activity against thrombin compared with that of reference compound dabigatran(IC50= 1.20 nM).Compounds 14k and 14m could act as candidate compounds for further studies on thrombin inhibitors.