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    J Med Chem. 2004 Aug 26;47(18):4494-506.

    Identification of 1,5-naphthyridine derivatives as a novel series of potent and selective TGF-beta type I receptor inhibitors.

    Gellibert F, Woolven J, Fouchet MH, Mathews N, Goodland H, Lovegrove V, Laroze A, Nguyen VL, Sautet S, Wang R, Janson C, Smith W, Krysa G, Boullay V, De Gouville AC, Huet S, Hartley D.

    Department of Medicinal Chemistry, GlaxoSmithKline, 25-27 Avenue du Québec, 91951 Les Ulis, France. fjg23217@gsk.com

    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.

    PMID: 15317461 [PubMed - indexed for MEDLINE]

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