Synthesis and biological evaluation of 1,2,4-trisubstituted imidazoles as inhibitors of transforming growth factor-β type I receptor (ALK5).
A series of 2-(6-methylpyridin-2-yl)-1H-imidazoles were synthesized and evaluated for ALK5 inhibitory activity in cell-based luciferase reporter assays. The compound 4-(((1-(benzo[d][1,3]dioxol-5-yl)-2-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)methyl)amino)benzenesulfonamide (27a) exhibited slightly higher inhibition (IC50=0.24μM) than SB431542 (IC50=0.35μM), a well known potent ALK5 inhibitor. The binding mode of 27a generated by flexible docking study shows that it fits well into the site cavity of ALK5 by forming several tight interactions.
Department of Chemistry, Capital Normal University, Beijing 100048, China. Electronic address: guocb@cnu.edu.cn.
Changbin
C
Guo
Chong
C
Zhang
Xingzhou
X
Li
Wei
W
Li
Zhongliang
Z
Xu
Liangliang
L
Bao
Yue
Y
Ding
Lili
L
Wang
Song
S
Li
D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology; D004149:Dioxoles / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D001549:Benzamides; D004149:Dioxoles; D007093:Imidazoles; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human
ALK5; Imidazole derivatives; Kinase inhibitor; Transforming growth factor β