Novel inhibitors of TGF-β1 and activin A signalling based on a 2-aryl-4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridine pharmacophore have been synthesised. Compounds containing phenyl or aromatic nitrogen heterocycle substituents inhibited both types of signalling with HEK-293T cells in culture, with a selectivity preference for TGF-β1. Synthetic compounds containing pyridin-3-yl, pyrazol-4-yl, pyrazol-1-yl or 1H-imidazoyl-1-yl substituents exhibited structural and functional attributes suitable for further investigation related to the development of more potent TGF-β inhibitors.
- Transforming growth factor-β
- activin A
- low molecular weight inhibitors
- structure-activity relationships
- ATP-competitive ALK4/ALK5 inhibitors
Ciayadi, R., Potdar, M., Walton, K. L., Harrison, C. A., Kelso, G. F., Harris, S. J., & Hearn, M. T. W. (2011). 2-Phenyl and 2-heterocyclic-4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridines as inhibitors of TGF-B1 and activin A signalling. Bioorganic and Medicinal Chemistry Letters, 21(18), 5642-5645. https://doi.org/10.1016/j.bmcl.2010.12.120