Synthesis and biological evaluation of 5-(fluoro-substituted-6-methylpyridin-2-yl)-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)imidazoles as inhibitors of transforming growth factor-β type I receptor kinase

Maddeboina Krishnaiah; Cheng Hua Jin; Yhun Yhong Sheen; Dae-Kee Kim

doi:10.1016/j.bmcl.2015.09.058

Synthesis and biological evaluation of 5-(fluoro-substituted-6-methylpyridin-2-yl)-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)imidazoles as inhibitors of transforming growth factor-β type I receptor kinase

Bioorg Med Chem Lett. 2015 Nov 15;25(22):5228-31. doi: 10.1016/j.bmcl.2015.09.058. Epub 2015 Sep 26.

Authors

Maddeboina Krishnaiah¹, Cheng Hua Jin¹, Yhun Yhong Sheen¹, Dae-Kee Kim²

Affiliations

¹ Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, 11-1 Daehyun-dong, Seodaemun-gu, Seoul 120-750, Republic of Korea.
² Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, 11-1 Daehyun-dong, Seodaemun-gu, Seoul 120-750, Republic of Korea. Electronic address: [email protected].

PMID: 26483198
DOI: 10.1016/j.bmcl.2015.09.058

Abstract

To further optimize a clinical candidate 5 (EW-7197), a series of 5-(3-, 4-, or 5-fluoro-substituted-6-methylpyridin-2-yl)-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)imidazoles 19a-l have been synthesized and evaluated for their TGF-β type I receptor kinase (ALK5) and p38α MAP kinase inhibitory activity in an enzyme assay. The 5-(5-fluoro-substituted-6-methylpyridin-2-yl)-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)imidazoles 19h-l displayed the similar level of potency to that of 5 against both ALK5 (IC50=7.68-13.70 nM) and p38α MAP kinase (IC50=1240-3370 nM). Among them, 19j inhibited ALK5 with IC50 value of 7.68 nM in a kinase assay and displayed 82% inhibition at 100 nM in a luciferase reporter assay.

Keywords: ALK5 inhibitor; Cancer; Fibrosis; Kinase assay; TGF-β.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Line
Enzyme Assays
Genes, Reporter
Humans
Imidazoles / chemical synthesis*
Imidazoles / pharmacology
Luciferases / genetics
Mitogen-Activated Protein Kinase 14 / antagonists & inhibitors
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / pharmacology
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Pyridines / chemical synthesis*
Pyridines / pharmacology
Receptor, Transforming Growth Factor-beta Type I
Receptors, Transforming Growth Factor beta / antagonists & inhibitors*
Triazoles / chemical synthesis*
Triazoles / pharmacology

Substances

Imidazoles
Protein Kinase Inhibitors
Pyridines
Receptors, Transforming Growth Factor beta
Triazoles
Luciferases
Protein Serine-Threonine Kinases
Mitogen-Activated Protein Kinase 14
Receptor, Transforming Growth Factor-beta Type I
TGFBR1 protein, human