title: 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.
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China.|Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, China.
authors.forename: Shaochi
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Dai
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China.|Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, China.
authors.forename: Yungen
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Pharmacology, China Pharmaceutical University, Nanjing, China.
authors.forename: Qiufang
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China.
authors.forename: Qihua
authors.initials: Q
authors.lastname: Zhu
authors.affiliation: Department of Pharmacology, China Pharmaceutical University, Nanjing, China.
authors.forename: Guoqing
authors.initials: G
authors.lastname: Gong
mesh_terms: D000818:Animals; D000991:Antithrombins / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D001665:Binding Sites; D018360:Crystallography, X-Ray; D000069604:Dabigatran / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D004195:Disease Models, Animal; D015195:Drug Design; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D008024:Ligands; D051379:Mice; D062105:Molecular Docking Simulation; D018716:Molecular Mimicry; D010974:Platelet Aggregation / Q000187:drug effects; D011485:Protein Binding; D011487:Protein Conformation; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D018570:Risk Assessment; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D020246:Venous Thrombosis / Q000097:blood / Q000517:prevention & control
chemical_list: D000991:Antithrombins; D008024:Ligands; D013917:Thrombin; D000069604:Dabigatran
keywords: Anti-platelet aggregation; Dabigatran; HTMP; Scaffold hopping; Thrombin inhibitors