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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.

Author information

  • 1Department of Medicinal Chemistry, GlaxoSmithKline, 25-27 Avenue du Qu├ębec, 91951 Les Ulis, France. fjg23217@gsk.com

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.

PMID:
15317461
DOI:
10.1021/jm0400247
[PubMed - indexed for MEDLINE]
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