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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:672.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Inhibition of Plasminogen Activator Inhibitor-1

Its Mechanism and Effectiveness on Coagulation and Fibrosis

Yuko Izuhara; Satoru Takahashi; Masaomi Nangaku; Shunya Takizawa; Hideyuki Ishida; Kiyoshi Kurokawa; Charles van Ypersele de Strihou; Noriaki Hirayama; Toshio Miyata

From the Institute of Medical Sciences (Y.I., K.K., T.M.), Tokai University, Kanagawa, Japan; the Department of Pathology (S.T.), University of Tsukuba School of Medicine, Tsukuba, Japan; the Division of Nephrology and Endocrinology (M.N.), University of Tokyo School of Medicine, Tokyo, Japan; the Divisions of Neurology (S.T.), Physiology (H.I.), and Basic Medical Science and Molecular Medicine (N.H.), Tokai University School of Medicine, Kanagawa, Japan; the Service de Nephrologie (C.v.Y.d.S.), Universite Catholique de Louvain, Brussels, Belgium; and the Division of Translational Medicine (T.M.), Center for Translational and Advanced Animal Research on Human Disease, Tohoku University School of Medicine, Japan.

Correspondence to Toshio Miyata, MD, PhD, Division of Translational Medicine, Center for Translational and Advanced Animal Research on Human Disease, Tohoku University School of Medicine, 2-1 Seiryo-Machi, Aoba-ku, Sendai, 980-8575, Japan. E-mail t-miyata{at}mail.tains.tohoku.ac.jp

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.

We identify novel orally active molecules able to enter, as a mock compound, into the strand 4 position (s4A) of the A β-sheet in plasminogen activator inhibitor (PAI)-1. In vitro they specifically inhibit the PAI-1 activity. In vivo, the most efficient molecule (TM5007) inhibits coagulation and prevents the fibrotic process.

Key Words: serpin • virtual screening • anticoagulation • antifibrosis • plasminogen activator inhibitor-1 inhibitor

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