Synthesis and biological evaluation of 4(5)-(6-alkylpyridin-2-yl)imidazoles as transforming growth factor-beta type 1 receptor kinase inhibitors.
A series of 4(5)-(6-alkylpyridin-2-yl)imidazoles 13a-p, 17a, and 17b have been synthesized and evaluated for ALK5 inhibitory activity in an enzyme assay and in cell-based luciferase reporter assays. The quinoxalinyl analogue 13e inhibited ALK5 phosphorylation with an IC50 of 0.012 muM and showed more than 90% inhibition at 0.05 muM in a luciferase reporter assay using HaCaT cells transiently transfected with p3TP-luc reporter construct. The binding mode of 13e generated by flexible docking studies shows that 13e fits well into the active site cavity of ALK5 by forming several tight interactions.
Kim
Dae-Kee
DK
College of Pharmacy, Ewha Womans University, 11-1 Daehyun-dong, Seodaemun-gu, Seoul 120-750, Korea. dkkim@ewha.ac.kr
Jang
Yoojeung
Y
Lee
Ho Soon
HS
Park
Hyun-Ju
HJ
Yoo
Jakyung
J
D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D018360:Crystallography, X-Ray; D017930:Genes, Reporter; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D007093:Imidazoles; D011725:Pyridines; D018125:Receptors, Transforming Growth Factor beta; D008156:Luciferases; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human