TM 5275

Product NameTM 5275
CAS1103926-82-4
MFC28H29ClN3NaO5
MW546
EINECS
MOL File1103926-82-4.mol

Chemical Properties

storage temp.	2-8°C
solubility	DMSO:20.0(Max Conc. mg/mL);36.77(Max Conc. mM) DMF:PBS (pH 7.2) (1:8):0.11(Max Conc. mg/mL);0.2(Max Conc. mM) DMF:33.0(Max Conc. mg/mL);60.66(Max Conc. mM)
form	powder
color	white to beige
InChIKey	JSHSGBIWNPQCQZ-UHFFFAOYSA-M
SMILES	O=C(COCC(NC1=C(C([O-])=O)C=C(Cl)C=C1)=O)N2CCN(C(C3=CC=CC=C3)C4=CC=CC=C4)CC2.[Na+]

Safety Information

RIDADR	UN 3077 9 / PGIII
WGK Germany	WGK 3
Storage Class	11 - Combustible Solids
Hazard Classifications	Acute Tox. 4 Oral Aquatic Acute 1

Usage And Synthesis

Description

TM5275 is an inhibitor of plasminogen activator inhibitor 1 (PAI-1; IC₅₀ = 6.95 μM), a serine-protease inhibitor involved in thrombosis. TM5275 inhibits formation of a complex consisting of tissue plasminogen activator (tPA), PAI-1, and GFP on vascular endothelial cells (VECs) in vitro, prolonging the time that tPA is retained on VECs. It also enhances fibrin clot dissolution and plasminogen accumulation in vitro and has antithrombotic effects in rat models of thrombosis. TM5275 (10 and 50 mg/kg) decreases blood clot weight in an arteriovenous shunt thrombosis model and increases the time to primary occlusion in a ferric chloride-treated carotid artery thrombosis model when used at doses of 1 and 3 mg/kg. In a cynomolgus monkey model of photochemical-induced arterial thrombosis, TM5275 (10 mg/kg) increases the time to primary occlusion. It does not affect platelet activity, activated partial thromboplastin time, prothrombin time, or prolong bleeding time.

Uses

TM 5275 Sodium Salt is a novel inhibitor of plasminogen activator inhibitor-1 (PAI-1), which provides antithrombitic benefits devoid of bleeding in primates.

Biochem/physiol Actions

TMS5275 is an orally available, potent and selective inhibitor of PAI-1 that delivers antithrombotic benefits devoid of bleeding effect in nonhuman primates.

in vivo

TM5275 exhibits a favorable pharmacokinetics profile and very low toxicity to mice and rats. In rat thrombosis models. Blood clot weights are significantly lower in rats administered 10 and 50 mg/kg of TM5275 (60.9±3.0 and 56.8±2.8 mg, respectively) than in vehicle-treated rats (72.5±2.0 mg). The antithrombotic effectiveness of TM5275 (50 mg/kg) is equivalent to that of ticlopidine (500 mg/kg), a reference antithrombotic compound. Plasma concentration of TM5275 reaches 17.5±5.2 μM after a dose of 10 mg/kg. TM5275 (5 mg/kg) combined with tPA (0.3 mg/kg) significantly enhances the antithrombotic effect of tPA (0.3 mg/kg) alone and provides a benefit similar to that of a high tPA dose (3 mg/kg)^[1].

storage

Store at +4°C

References

[1] YUKO IZUHARA. A novel inhibitor of plasminogen activator inhibitor-1 provides antithrombotic benefits devoid of bleeding effect in nonhuman primates.[J]. Journal of Cerebral Blood Flow and Metabolism, 2010, 30 5: 904-912. DOI: 10.1038/jcbfm.2009.272
[2] HIDEKI YASUI . TM5275 prolongs secreted tissue plasminogen activator retention and enhances fibrinolysis on vascular endothelial cells[J]. Thrombosis research, 2013, 132 1: Pages 100-105. DOI: 10.1016/j.thromres.2013.04.003

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