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

• Published in: Journal of cerebral blood flow and metabolism Vol. 30; no. 5; pp. 904 - 912
• Main Authors: Izuhara, Yuko, Yamaoka, Nagahisa, Kodama, Hidehiko, Dan, Takashi, Takizawa, Shunya, Hirayama, Noriaki, Meguro, Kanji, van Ypersele de Strihou, Charles, Miyata, Toshio
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.05.2010; Nature Publishing Group; Sage Publications Ltd
• Subjects: 4-Aminobenzoic Acid - chemical synthesis; 4-Aminobenzoic Acid - chemistry; 4-Aminobenzoic Acid - pharmacology; 4-Aminobenzoic Acid - therapeutic use; Animals; Biological and medical sciences; Blood. Blood coagulation. Reticuloendothelial system; Cynomolgus; Disease Models, Animal; Drug Design; Female; Fibrinolytic Agents - chemical synthesis; Fibrinolytic Agents - chemistry; Fibrinolytic Agents - pharmacology; Fibrinolytic Agents - therapeutic use; Hemorrhage - drug therapy; Humans; Macaca fascicularis; Male; Medical sciences; Mice; Models, Molecular; Molecular Structure; Neurology; Original; para-Aminobenzoates; Pharmacology. Drug treatments; Piperazines - chemical synthesis; Piperazines - chemistry; Piperazines - pharmacology; Piperazines - therapeutic use; Plasminogen Activator Inhibitor 1 - chemistry; Plasminogen Activator Inhibitor 1 - metabolism; Primates; Protein Conformation; Rats; Rats, Sprague-Dawley; Rats, Wistar; Serine Proteinase Inhibitors - chemistry; Serine Proteinase Inhibitors - metabolism; Structure-Activity Relationship; Thrombosis - drug therapy; Ticlopidine - pharmacology; Ticlopidine - therapeutic use; Tissue Plasminogen Activator - therapeutic use; Vascular diseases and vascular malformations of the nervous system; bleeding; cynomolgus monkey; thrombosis; tissue plasminogen activator; PAI-1 inhibitor; Nervous system diseases; Serine endopeptidases; Enzyme; Monkey; Cardiovascular disease; Hemorrhage; Thrombosis; t-Plasminogen activator; Cerebral disorder; Vascular disease; Peptidases; Plasminogen activator inhibitor 1; Vertebrata; Mammalia; Animal; Central nervous system disease; Primates; Hydrolases; Cerebrovascular disease
• ISSN: 0271-678X; 1559-7016
• DOI: 10.1038/jcbfm.2009.272

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.