TK-129 is an orally active, potent inhibitor of KDM5B with IC 50 of 44 nM that is low-toxicity. TK-129 shows cardioprotective effects by inhibiting KDM5B and blocking the KDM5B -associated Wnt pathway. TK-129 can be used in cardiovascular disease studies which reduce isoprenaline-induced myocardial remodelling and fibrosis in vivo as well as reduce ang II-induced activation of cardiac fibroblasts in vitro [1].

TK-129 mediates inhibition of KDM5B activity significantly reduces the activation, migration, and proliferation of myofibroblasts induced by Ang II in vitro [1]. TK-129 (10 μM; 48 h) shows low cytotoxicity in NRCFs and NRCMs [1]. TK-129 (0.1, 0.2, 0.3, 0.4, 0.5 μM; 48 h) can engage toand inhibit KDM5B activity in NRCFs [1]. Cell Cytotoxicity Assay [1] Cell Line: NRCFs and NRCMs Concentration: 10 μM Incubation Time: 48 h Result: Exhibited the cell survival rates were almost more than 90%. Western Blot Analysis [1] Cell Line: NRCFs Concentration: 0.1, 0.2, 0.3, 0.4, 0.5 μM Incubation Time: 48 h Result: Increased the expression level of KDM5B substrate H3K4me3 protein in a concentration-dependent manner.

TK-129 (2 g/kg; p.o.; single) shows good bio-safety in mice [1]. TK-129 (50 mg/kg; p.o.; twice daily for 24 days) effectively reduces isoproterenol-induced pathological myocardial remodeling in vivo [1]. TK-129 (2 or 10 mg/kg; i.v. or p.o.; single) demonstrates favorable PK properties in vivo [1]. Animal Model: Wild C57BL/6 mice (8 to 10-week-old; half male and half female) [1]. Dosage: 2 g/kg Administration: Oral gavage, single. Result: Exhibited all mice in the acute toxicity group survived and gained weight normally, after 2 weeks. Animal Model: C57BL/6 mice (isoproterenol (ISO)-induced) [1]. Dosage: 50 mg/kg Administration: Oral gavage, twice daily for 24 days. Result: Alleviated myocardial remodeling induced by ISO in vivo. Animal Model: Male SD Rats (223.5-265.1 g) [1]. Dosage: 2 mg/kg (for i.v.); 10 mg/kg (for p.o.). Administration: Intravenous injection or oral gavage; single. Result: 1.19 Pharmacokinetic Parameters of TK-129 in Male SD Rats [1]. PO (10 mg/kg) IV (2 mg/kg) CL (L/h/kg) 9.9 4.2 V ss (L/kg) 33.4 2.7 T 1/2 (h) 2.4 0.4 T max (h) 0.4 - C max (ng/mL) 709.7 1229.1 AUC 0-24 (ng/mL h) 1038.2 479.6 F (%) 42.37 -