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

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

  • J Med Chem. 2004 Aug 26;47(18):4494-506. doi: 10.1021/jm0400247.
Françoise Gellibert 1,  James Woolven,  Marie-Hélène Fouchet,  Neil Mathews,  Helen Goodland,  Victoria Lovegrove,  Alain Laroze,  Van-Loc Nguyen,  Stéphane Sautet,  Ruolan Wang,  Cheryl Janson,  Ward Smith,  Gaël Krysa,  Valérie Boullay,  Anne-Charlotte De Gouville,  Stéphane Huet,  David Hartley
Affiliations

Affiliation

  • 1 Department of Medicinal Chemistry, GlaxoSmithKline, 25-27 Avenue du Québec, 91951 Les Ulis, France. [email protected]
PMID: 15317461 DOI: 10.1021/jm0400247
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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