Synthesis and biological evaluation of novel benzo[c] [1,2,5]thiadiazol-5-yl and thieno [3,2-c] - pyridin-2-yl imidazole derivatives as ALK5 inhibitors

被引：25

作者：

Guo, Zhen ^{[1
]}

Song, Xiaowei ^{[4
]}

Zhao, Li-Min ^{[1
]}

Piao, Ming Guan ^{[1
]}

Quan, Jishan ^{[1
,3
]}

Piao, Hu-Ri ^{[1
]}

Jin, Cheng Hua ^{[1
,2
]}

机构：

[1] Yanbian Univ, Coll Pharm, Yanji 133002, Peoples R China

[2] Yanbian Univ, Mol Med Res Ctr, Minist Educ, Key Lab Nat Resources Changbai Mt & Funct Mol, Yanji 133002, Peoples R China

[3] Yanbian Univ, Coll Pharm, Dept Pharmaceut, Yanji 133002, Peoples R China

[4] Yanbian Univ Hosp, Dept Radiol, Yanji 133002, Peoples R China

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2019年 / 29卷 / 16期

基金：

美国国家科学基金会;

关键词：

ALK5; TGF-beta; Imidazole; Inhibitors; ADMET; GROWTH-FACTOR-BETA; KINASE INHIBITOR; SMALL-MOLECULE; GALUNISERTIB; POTENT; LY2157299; DESIGN;

D O I：

10.1016/j.bmcl.2019.07.015

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Transforming growth factor (TGF-beta), a key mediator of tumor growth and metastasis, has been recognized as an important cancer drug target. A series of benzo[c][1,2,5]thiadiazol-5-yl imidazoles (14a-g) and thieno [3,2-c]-pyridin-2-yl imidazoles (20a-g) were designed, synthesized, and evaluated for their activin receptor-like kinase 5 (ALK5) activities. Among these compounds, 14c showed the highest activity (IC50 = 0.008 mu M) against ALK5 kinase, which was 16.1-fold and 1.8-fold higher than those of positive control compounds LY-2157 299 (IC50 = 0.129 mu M) and EW-7 197 (IC50 = 0.014 mu M), respectively. Compound 14g (350) showed the highest selectivity index of ALK5 against p38 alpha MAP kinase, which was significantly higher than that of positive control compounds LY-2157 299 (4) and EW-7 197 (211). The inhibitory effects of compound 14c on TGF-beta-induced Smad signaling and cell motility were studied in SPC-A1, HepG2 and HUVEC cells using western blot analysis and wound healing assay. ADMET prediction analysis showed that compounds 14c and 14g had good pharmacokinetics and drug-likeness behaviors.

引用

页码：2070 / 2075

页数：6