Discovery of Novel Pyrazole-Based KDM5B Inhibitor TK - 129 and Its Protective Effects on Myocardial Remodeling and Fibrosis.

Lysine-specific demethylase 5B (KDM5B) has been recognized as a potential drug target for cardiovascular diseases. In this work, we first found that the KDM5B level was increased in mouse hearts after transverse aortic constriction (TAC) and in Ang II-induced activated cardiac fibroblasts. Structure-based design and further optimizations led to the discovery of highly potent pyrazole-based KDM5B inhibitor TK - 129 (IC 50 = 0.044 μM). TK - 129 reduced Ang II-induced activation of cardiac fibroblasts in vitro , exhibited good PK profile ( F = 42.37%), and reduced isoprenaline-induced myocardial remodeling and fibrosis in vivo . Mechanistically, we found that KDM5B up-regulation in cardiac fibroblast activation was associated with the activation of Wnt-related pathway. The protective effects of TK - 129 were associated with its KDM5B inhibition and blocking KDM5B-related Wnt pathway activation. Taken together, TK - 129 may represent a novel KDM5-targeting lead compound for cardiac remodeling and fibrosis.