Abstract
| Original language | English |
|---|---|
| Article number | 110 |
| Pages (from-to) | 181-194 |
| Number of pages | 14 |
| Journal | European Journal of Medicinal Chemistry |
| DOIs | |
| Publication status | Published - 3 Mar 2016 |
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Keywords
- Coumarins; Factor XIIa; Factor XII; FXII; antithrombotic agents; benzopyrans
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Synthesis, evaluation and structure-activity relationship of new 3-carboxamide coumarins as FXIIa inhibitors. / Bouckaert, Charlotte; Serra, Silvia; Rondelet, Grégoire; Dolusic, Eduard; Wouters, Johan; Dogne, Jean-Michel; Frédérick, Raphaël; Pochet, Lionel.
In: European Journal of Medicinal Chemistry, 03.03.2016, p. 181-194.Research output: Contribution to journal › Article
TY - JOUR
T1 - Synthesis, evaluation and structure-activity relationship of new 3-carboxamide coumarins as FXIIa inhibitors
AU - Bouckaert, Charlotte
AU - Serra, Silvia
AU - Rondelet, Grégoire
AU - Dolusic, Eduard
AU - Wouters, Johan
AU - Dogne, Jean-Michel
AU - Frédérick, Raphaël
AU - Pochet, Lionel
PY - 2016/3/3
Y1 - 2016/3/3
N2 - 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.
AB - 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.
KW - Coumarins; Factor XIIa; Factor XII; FXII; antithrombotic agents; benzopyrans
U2 - 10.1016/j.ejmech.2016.01.023
DO - 10.1016/j.ejmech.2016.01.023
M3 - Article
SP - 181
EP - 194
JO - European journal of medicinal chemistry / Chimica therapeutica
JF - European journal of medicinal chemistry / Chimica therapeutica
SN - 0223-5234
M1 - 110
ER -