Synthesis and biological evaluation of 4-(pyridin-4-oxy)-3-(3,3-difluorocyclobutyl)-pyrazole derivatives as novel potent transforming growth factor-β type 1 receptor inhibitors
作者:Guofeng Xu、Yan Zhang、Hai Wang、Zhuang Guo、Xiaowei Wang、Xue Li、Shaohua Chang、Tianwen Sun、Zhuangzhuang Yu、Tianwei Xu、Liwen Zhao、Yazhou Wang、Wenying Yu
DOI:10.1016/j.ejmech.2020.112354
日期:2020.7
factor β (TGF-β) type 1 receptor (ALK5) provides a feasible approach for the treatment of fibrotic diseases and malignant tumors. In this study, we designed and synthesized a new series of 4-(pyridin-4-oxy)-3-(3,3-difluorocyclobutyl)-pyrazole derivatives, and evaluated biologically as TGF-β type 1 receptor inhibitors. The most potent compound 15r inhibited the ALK5 enzyme and NIH3T3 cell viability with IC50
抑制转化生长因子β(TGF-β)1型受体(ALK5)提供了一种治疗纤维化疾病和恶性肿瘤的可行方法。在这项研究中,我们设计并合成了一系列新的4-(吡啶-4-氧基)-3-(3,3-二氟环丁基)-吡唑衍生物,并作为TGF-β1型受体抑制剂进行了生物学评估。最有效的化合物15r抑制ALK5酶和NIH3T3细胞的活力,IC50值分别为44和42.5 nM。与LY-3200882相比,化合物15r还具有更好的口服血浆暴露和出色的生物利用度,并且在CT26异种移植小鼠模型中体内抑制了65.7%的肿瘤生长。