title: A novel inhibitor of plasminogen activator inhibitor-1 provides antithrombotic benefits devoid of bleeding effect in nonhuman primates.
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 arterial venous 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.
authors.affiliation: Center for Translational and Advanced Research, Tohoku University Graduate School of Medicine, Miyagi, Aoba-ku, Sendai, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Izuhara
authors.forename: Nagahisa
authors.initials: N
authors.lastname: Yamaoka
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Kodama
authors.forename: Takashi
authors.initials: T
authors.lastname: Dan
authors.forename: Shunya
authors.initials: S
authors.lastname: Takizawa
authors.forename: Noriaki
authors.initials: N
authors.lastname: Hirayama
authors.forename: Kanji
authors.initials: K
authors.lastname: Meguro
authors.forename: Charles
authors.initials: C
authors.lastname: van Ypersele de Strihou
authors.forename: Toshio
authors.initials: T
authors.lastname: Miyata
mesh_terms: D010129:4-Aminobenzoic Acid / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D004195:Disease Models, Animal; D015195:Drug Design; D005260:Female; D005343:Fibrinolytic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D006470:Hemorrhage / Q000188:drug therapy*; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D017395:Plasminogen Activator Inhibitor 1 / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013927:Thrombosis / Q000188:drug therapy*; D013988:Ticlopidine / Q000494:pharmacology / Q000627:therapeutic use; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use; D062366:para-Aminobenzoates
chemical_list: C549556:5-chloro-2-(((2-(4-(diphenylmethyl)piperazin-1-yl)-2-oxoethoxy)acetyl)amino)benzoate; D005343:Fibrinolytic Agents; D010879:Piperazines; D017395:Plasminogen Activator Inhibitor 1; D015842:Serine Proteinase Inhibitors; D062366:para-Aminobenzoates; D010959:Tissue Plasminogen Activator; D013988:Ticlopidine; D010129:4-Aminobenzoic Acid