TY - JOUR
T1 - 3,6-Disubstituted coumarins as mechanism-based inhibitors of thrombin and factor Xa
AU - Frédérick, R.
AU - Robert, S.
AU - Masereel, B.
AU - Pochet, L.
AU - Pirotte, B.
AU - Charlier, C.
AU - De Ruyck, J.
AU - Wouters, J.
N1 - MEDLINE® is the source for the MeSH terms of this document.
PY - 2005/12/1
Y1 - 2005/12/1
N2 - In this work, coumarins were screened on thrombin (THR) and factor Xa (FXa), two of the most promising targets for the development of anticoagulant drugs. This allowed us to highlight compound 30, characterized by a 2,5-dichlorophenyl ester in the 3-position and a chloromethyl moiety in the 6-position, as a very potent THR inhibitor (k /K = 37 000 M s ). Moreover, this compound exhibits good selectivity over FXa (168-fold) and trypsin (54-fold). The mechanism of inactivation was investigated in this series and significantly differs from that previously observed with α-chymotrypsin. Indeed, the addition of hydrazine on the THR-inhibitor complex promotes a partial induced THR reactivation. This reactivation, confirmed by LC/MS, showed the resurgence of the native THR and a new dihydrazide complex. Docking experiments were then efficiently used to explain the trends observed in the enzymatic assays as well as to corroborate the postulated inhibition mechanism. Finally, the cell permeability of our derivatives was estimated using a computational approach.
AB - In this work, coumarins were screened on thrombin (THR) and factor Xa (FXa), two of the most promising targets for the development of anticoagulant drugs. This allowed us to highlight compound 30, characterized by a 2,5-dichlorophenyl ester in the 3-position and a chloromethyl moiety in the 6-position, as a very potent THR inhibitor (k /K = 37 000 M s ). Moreover, this compound exhibits good selectivity over FXa (168-fold) and trypsin (54-fold). The mechanism of inactivation was investigated in this series and significantly differs from that previously observed with α-chymotrypsin. Indeed, the addition of hydrazine on the THR-inhibitor complex promotes a partial induced THR reactivation. This reactivation, confirmed by LC/MS, showed the resurgence of the native THR and a new dihydrazide complex. Docking experiments were then efficiently used to explain the trends observed in the enzymatic assays as well as to corroborate the postulated inhibition mechanism. Finally, the cell permeability of our derivatives was estimated using a computational approach.
UR - http://www.scopus.com/inward/record.url?scp=28144446421&partnerID=8YFLogxK
U2 - 10.1021/jm050448g
DO - 10.1021/jm050448g
M3 - Article
AN - SCOPUS:28144446421
SN - 0022-2623
VL - 48
SP - 7592
EP - 7603
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 24
ER -