TM5441

TM5441 is an orally bioavailable inhibitor of plasminogen activator inhibitor 1 (PAI-1), a serine-protease inhibitor involved in thrombosis. It decreases survival of HT1080, HCT116, Daoy, MDA-MB-231, and Jurkat cancer cells with IC50 values ranging from 13.9 to 51.1 uM. TM5441 inhibits branching of human umbilical vein endothelial cells (HUVECs) in a vasculature assay in vitro when used at a concentration of 50 uM but does not affect HUVEC survival or apoptosis. It also disrupts tumor vasculature in HT1080 and HCT116 mouse xenograft models when used at a dose of 20 mg/kg per day. TM5441 prevents hypertension and cardiac hypertrophy and reduces periaortic fibrosis induced by L-NAME . It protects against high-fat diet-induced non-alcoholic fatty liver disease (NAFLD) in mice when administered concurrently with a high-fat diet or after glucose tolerance has developed. TM5441 also increases median lifespan by 4-fold and reduces signs of senescence in Klotho-deficient mice, a mouse model of aging.