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.

Decreased expression of the plasminogen activator inhibitor type 1 is involved in degradation of extracellular matrix surrounding cervical cancer stem cells

“…After sorting, 1x10 5 cells were seeded and cultured for 24 h. Then, medium was changed to DMEM with or without 10 nM TM5275 for 24 h, and the supernatants were collected (43). As shown in Fig.…”

Characterization of a Small Molecule Inhibitor of Plasminogen Activator Inhibitor Type 1 That Accelerates the Transition into the Latent Conformation

“…Although an inhibitor for PAI-1 that neutralizes the activity of both PAI-1 in complex with VN and of free PAI-1 may yield the most effective inhibition, it is still possible that selective inhibition of free PAI-1 could provide therapeutic benefit. Several studies with inhibiting antibodies and small molecules against PAI-1 have shown effects in different animal models of fibrinolysis (33)(34)(35)(36)(37)(38)(39)(40)(41)(42). We are not aware of a PAI-1 inhibitor that has been tested in patients, but the low molecular weight PAI-1 inhibitor PAI-749 (diaplasinin) has been tested ex vivo in human blood using the Badimon chamber and was found not to have an effect on in vitro or ex vivo thrombus formation or fibrinolysis in the presence or absence of tPA (43,44).…”

Inhibitory effect of water extractive components from heshiko and narezushi on plasma PAI-1 activity in rats

“…[2][3][4][5][6] It is already known that small molecules including peptides can inhibit PAI-1 activity by entering into the cleft of the PAI-1 molecule as a mock substance. [25][26][27][28] As the extracts from heshiko and narezushi contain a large amount of peptides, 19,20 therefore, direct PAI-1 inhibition by heshiko and narezushi extracts is proposed as a possible mechanism to explain the reduced PAI-1 activity of rats shown in Table 3. Next, the PAI-1 inhibitory activity of the heshiko and narezushi extracts was examined by mixing active PAI-1 solution with the heshiko and narezushi extracts.…”

“…shown to be PAI-1 inhibitors, 26,27 we examined changes in the PAI-1 inhibitory activity of these extracts by digestion with proteases.…”

“…As for the PAI-1 inhibitor(s), various low molecular weight compounds have been proved using structural analysis; 26,27 however, there are few reports dealing with PAI-1 inhibitors derived from foodstuffs. Peptides have been listed as PAI-1 inhibitors, 25 and heshiko and narezushi contain large amounts of peptides as a result of the long fermentation and aging processes involved in their production.…”