NDLI: A novel inhibitor of plasminogen activator inhibitor-1 provides antithrombotic benefits devoid of bleeding effect in nonhuman primates

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Year: 2010, Volume: 30, Issue: 4

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A novel inhibitor of plasminogen activator inhibitor-1 provides antithrombotic benefits devoid of bleeding effect in nonhuman primates

Content Provider	PubMed Central
Author	Yuko, Izuhara Yamaoka, Nagahisa Kodama, Hidehiko Dan, Takashi Takizawa, Shunya Hirayama, Noriaki Meguro, Kanji Van Ypersele De Strihou, Charles Miyata, Toshio
Copyright Year	2010
Abstract	Inhibition of plasminogen activator inhibitor (PAI)-1 is useful to treat several disorders including thrombosis. An inhibitor of PAI-1 (TM5275) was newly identified by an extensive study of structure-activity relationship based on a lead compound (TM5007) which was obtained through virtual screening by docking simulations. Its antithrombotic efficacy and adverse effects were tested in vivo in rats and nonhuman primates (cynomolgus monkey). TM5275, administered orally in rats (1 to 10 mg/kg), has an antithrombotic effect equivalent to that of ticlopidine (500 mg/kg) in an arterialvenous shunt thrombosis model and to that of clopidogrel (3 mg/kg) in a ferric chloride-treated carotid artery thrombosis model. TM5275 does not modify activated partial thromboplastin time and prothrombin time or platelet activity and does not prolong bleeding time. Combined with tissue plasminogen activator, TM5275 improves the latter's therapeutic efficacy and reduces its adverse effect. Administered to a monkey model of photochemical induced arterial thrombosis, TM5275 (10 mg/kg) has the same antithrombotic effect as clopidogrel (10 mg/kg), without enhanced bleeding. This study documents the antithrombotic benefits of a novel, more powerful, PAI-1 inhibitor in rats and, for the first time, in nonhuman primates. These effects are obtained without adverse effect on bleeding time.
Related Links	http://dx.doi.org/10.1038/jcbfm.2009.272
Ending Page	912
Page Count	9
Starting Page	904
File Format	PDF
ISSN	15597016
e-ISSN	15597016
Journal	Journal of Cerebral Blood Flow and Metabolism: Official Journal of the International Society of Cerebral Blood Flow and Metabolism
Issue Number	5
Volume Number	30
Language	English
Publisher	Nature Publishing Group
Publisher Date	2010-05-01
Access Restriction	Open
Rights Holder	Nature Publishing Group
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Neurology Neurology (clinical) Cardiology and Cardiovascular Medicine

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