Synthesis, evaluation and structure-activity relationship of new 3-carboxamide coumarins as FXIIa inhibitors

被引：44

作者：

Bouckaert, Charlotte ^{[1
]}

Serra, Silvia ^{[1
]}

Rondelet, Gregoire ^{[2
]}

Dolusic, Eduard ^{[3
]}

Wouters, Johan ^{[2
]}

Dogne, Jean-Michel ^{[1
]}

Frederick, Raphael ^{[4
]}

Pochet, Lionel ^{[1
]}

机构：

[1] Univ Namur, Namur Res Inst Life Sci NARILIS, Namur Med & Drug Innovat Ctr NAMEDIC, Dept Pharm, 61 Rue Bruxelles, B-5000 Namur, Belgium

[2] Univ Namur, Namur Res Inst Life Sci NARILIS, Namur Med & Drug Innovat Ctr NAMEDIC, Dept Chem, 61 Rue Bruxelles, B-5000 Namur, Belgium

[3] Univ Namur, Namur Res Inst Life Sci NARILIS, Namur Med & Drug Innovat Ctr NAMEDIC, Dept Organ Chem, 61 Rue Bruxelles, B-5000 Namur, Belgium

[4] Catholic Univ Louvain, LDRI, Med Chem Res Grp CMFA, 73 Ave E Mounier, B-1200 Brussels, Belgium

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2016年 / 110卷

关键词：

Coumarins; Factor XIIa; Factor XII; FXII; Antithrombotic agents; Benzopyrans; MECHANISM-BASED INHIBITORS; FACTOR-XII; THROMBIN INHIBITORS; ALPHA-CHYMOTRYPSIN; INTRINSIC PATHWAY; SWISS-MODEL; COAGULATION; DESIGN; POTENT; TARGETS;

D O I：

10.1016/j.ejmech.2016.01.023

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Inhibitors of the coagulation factor XIIa (FXIIa) are attractive to detail the roles of this protease in hemostasis and thrombosis, to suppress artifact due to contact pathway activation in blood coagulation assays, and they are promising as antithrombotic therapy. The 3-carboxamide coumarins have been previously described as small-molecular-weight FXIIa inhibitors. In this study, we report a structure activity relationship (SAR) study around this scaffold with the aim to discover new selective FXIIa inhibitors with an improved physico-chemical profile. To better understand these SAR, docking experiments were undertaken. For this purpose, we built an original hybrid model of FXIIa. This model has the advantage to gather the best features from the recently published crystal structure of FXIIa in its zymogen form and a more classical homology model. Results with the hybrid model are encouraging as they help understanding the activity and selectivity of our best compounds. (C) 2016 Elsevier Masson SAS. All rights reserved.

引用

页码：181 / 194

页数：14

共 52 条

[1] The legend of 4-aminocoumarin: use of the Delepine reaction for synthesis of 4-iminocoumarin [J].