TY - JOUR
T1 - Inhibition of plasminogen activator inhibitor-1
T2 - Its mechanism and effectiveness on coagulation and fibrosis
AU - Izuhara, Yuko
AU - Takahashi, Satoru
AU - Nangaku, Masaomi
AU - Takizawa, Shunya
AU - Ishida, Hideyuki
AU - Kurokawa, Kiyoshi
AU - Van Ypersele De Strihou, Charles
AU - Hirayama, Noriaki
AU - Miyata, Toshio
PY - 2008/4
Y1 - 2008/4
N2 - OBJECTIVE - Serine protease inhibitors (serpin) play a central role in various pathological processes including coagulation, fibrinolysis, malignancy, and inflammation. Inhibition of serpins may prove therapeutic. As yet, however, only very few small molecule serpin inhibitors have been reported. For the first time, we apply a new approach of virtual screening to discover novel, orally active, small molecule serpin inhibitors and report their effectiveness. METHODS AND RESULTS - We focused on a clinically important serpin, plasminogen activator inhibitor-1 (PAI-1), whose crystal structure has been described. We identify novel, orally active molecules able to enter into the strand 4 position (s4A) of the A β-sheet of PAI-I as a mock compound. In vitro they specifically inhibit the PAI-1 activity and enhance fibrinolysis activity. In vivo the most effective molecule (TM5007) inhibits coagulation in 2 models: a rat arteriovenous (AV) shunt model and a mouse model of ferric chloride-induced testicular artery thrombosis. It also prevents the fibrotic process initiated by bleomycin in mouse lung. CONCLUSIONS - The present study demonstrates beneficial in vitro and in vivo effects of novel PAI-1 inhibitors. Our methodology proves to be a useful tool to obtain effective inhibitors of serpin activity.
AB - OBJECTIVE - Serine protease inhibitors (serpin) play a central role in various pathological processes including coagulation, fibrinolysis, malignancy, and inflammation. Inhibition of serpins may prove therapeutic. As yet, however, only very few small molecule serpin inhibitors have been reported. For the first time, we apply a new approach of virtual screening to discover novel, orally active, small molecule serpin inhibitors and report their effectiveness. METHODS AND RESULTS - We focused on a clinically important serpin, plasminogen activator inhibitor-1 (PAI-1), whose crystal structure has been described. We identify novel, orally active molecules able to enter into the strand 4 position (s4A) of the A β-sheet of PAI-I as a mock compound. In vitro they specifically inhibit the PAI-1 activity and enhance fibrinolysis activity. In vivo the most effective molecule (TM5007) inhibits coagulation in 2 models: a rat arteriovenous (AV) shunt model and a mouse model of ferric chloride-induced testicular artery thrombosis. It also prevents the fibrotic process initiated by bleomycin in mouse lung. CONCLUSIONS - The present study demonstrates beneficial in vitro and in vivo effects of novel PAI-1 inhibitors. Our methodology proves to be a useful tool to obtain effective inhibitors of serpin activity.
KW - Anticoagulation
KW - Antifibrosis
KW - Plasminogen activator inhibitor-1 inhibitor
KW - Serpin
KW - Virtual screening
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U2 - 10.1161/ATVBAHA.107.157479
DO - 10.1161/ATVBAHA.107.157479
M3 - Article
C2 - 18239154
AN - SCOPUS:42249111398
VL - 28
SP - 672
EP - 677
JO - Arteriosclerosis, Thrombosis, and Vascular Biology
JF - Arteriosclerosis, Thrombosis, and Vascular Biology
SN - 1079-5642
IS - 4
ER -