TM5441 is an orally bioavailable fibrinogen activator inhibitor-1 inhibitor that inhibits several cancer cell lines with IC50 values ranging from 13.9 to 51.1 μM.It induces intrinsic cell death in several human cancer cells and attenuates Nω-nitro-1-arginine methyl ester-induced cardiac hypertension and vascular senescence.

Tumor cells:9.7～60.3 μM

METHODS: TM5441 (1-100μM) was used to further study the survival of HT1080, HCT116, Daoy, MDA-MB-231 and Jurkat.
RESULTS Cell viability treated with TM5441 significantly decreased in a dose-dependent manner by 50%, ranging between 13.9 and 51.1μM.[2]
METHODS: Cultures of human endothelial cells EA.hy926 were pretreated with TM5441 (10 μM) for 24 h and then treated with doxorubicin (Dox) in triplicate for 4 days. Total protein and RNA were collected from three independently treated wells and combined to explore the protective effect of TM5441 on Dox-induced cellular senescence.
RESULTS TM5441 treatment inhibited Dox-induced expression levels of p53, PAI-1, p16, p21 and IGFBP3 in human endothelial cells. [3]

METHODS: High-fat diet (HFD)-fed C57BL/6J mice were treated with 20 mg/kg of TM5441 daily to study the effect of TM5441, an oral PAI-1 inhibitor that lacks bleeding risk, on HFD-induced NAFLD.
RESULTS Early and delayed treatment with TM5441 reduced hepatic steatosis, and both strategies abolished hepatic insulin resistance and mitochondrial dysfunction, manifested by enhanced p-Akt and p-GSK3β, reduced p-JNK signaling, and p-AMPK and PGC-1α activation. [1]

TM5441 is dissolved with DMSO at a stock concentration of 50 mM.HT1080, HCT116, Daoy, MDA-MB-231 and Jurkat cells are treated with 0-100 μM TM5441 for 48 hours at 37°C. Cell viability is measured by MTT assay.

TM5441 is prepared in 0.5% carboxymethyl cellulose.Mice: TM5275 at 50 mg/kg/day and TM5441 at 10 mg/kg/day were orally administered in control and diabetic mice for 16 weeks. Mice were monitored at least once a day. At the end, blood is collected for measurement of plasma glucose and creatinine, urine for protein measurement, and kidneys for immunohistochemical analysis.