State Key Laboratory of Esophageal Cancer Prevention and Treatment; Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, P. R. China.
J Med Chem. 2022 Oct 13;65(19):12979-13000. doi: 10.1021/acs.jmedchem.2c00797. Epub 2022 Sep 16.
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 - (IC = 0.044 μM). - reduced Ang II-induced activation of cardiac fibroblasts , exhibited good PK profile ( = 42.37%), and reduced isoprenaline-induced myocardial remodeling and fibrosis . Mechanistically, we found that KDM5B up-regulation in cardiac fibroblast activation was associated with the activation of Wnt-related pathway. The protective effects of - were associated with its KDM5B inhibition and blocking KDM5B-related Wnt pathway activation. Taken together, - may represent a novel KDM5-targeting lead compound for cardiac remodeling and fibrosis.
赖氨酸特异性脱甲基酶 5B（KDM5B）已被认为是心血管疾病的潜在药物靶点。在这项工作中，我们首先发现，在横主动脉缩窄（TAC）和 Ang II 诱导的激活心肌成纤维细胞后，小鼠心脏中的 KDM5B 水平增加。基于结构的设计和进一步优化导致发现了高活性的吡唑基 KDM5B 抑制剂 -（IC = 0.044 μM）。- 减少 Ang II 诱导的心肌成纤维细胞激活，表现出良好的 PK 特征（= 42.37%），并减少异丙肾上腺素诱导的心肌重构和纤维化。在机制上，我们发现，在心肌成纤维细胞激活中 KDM5B 的上调与 Wnt 相关途径的激活有关。- 的保护作用与其 KDM5B 抑制和阻断 KDM5B 相关 Wnt 途径激活有关。总之，- 可能代表一种新型的针对心肌重构和纤维化的 KDM5 靶向先导化合物。
