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

Yuko Izuhara, Nagahisa Yamaoka, Hidehiko Kodama, Takashi Dan, Shunya Takizawa, Noriaki Hirayama, Kanji Meguro, Charles Van Ypersele De Strihou, Toshio Miyata

Research output: Contribution to journalArticle

75 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)904-912
Number of pages9
JournalJournal of Cerebral Blood Flow and Metabolism
Volume30
Issue number5
DOIs
Publication statusPublished - 2010 May

Keywords

  • Bleeding
  • Cynomolgus monkey
  • PAI-1 inhibitor
  • Thrombosis
  • Tissue plasminogen activator

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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