Identification of 1,5-Naphthyridine Derivatives as a Novel Series of Potent and Selective TGF-β Type I Receptor Inhibitors
Journal of Medicinal Chemistry2004Vol. 47(18), pp. 4494–4506
Citations Over TimeTop 15% of 2004 papers
Françoise Gellibert, James M. Woolven, Marie-Hélène Fouchet, Neil Mathews, Helen Goodland, V.L.H. Lovegrove, Alain Laroze, Van-Loc Nguyen, Stéphane Sautet, Ruolan Wang, Cheryl A. Janson, Ward W. Smith, Gaël Krysa, Valérie Boullay, Anne‐Charlotte de Gouville, Stéphane Huet, David J. Hartley
Abstract
Optimization of the screening hit 1 led to the identification of novel 1,5-naphthyridine aminothiazole and pyrazole derivatives, which are potent and selective inhibitors of the transforming growth factor-beta type I receptor, ALK5. Compounds 15 and 19, which inhibited ALK5 autophosphorylation with IC50 = 6 and 4 nM, respectively, showed potent activities in both binding and cellular assays and exhibited selectivity over p38 mitogen-activated protein kinase. The X-ray crystal structure of 19 in complex with human ALK5 is described, confirming the binding mode proposed from docking studies.
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