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Rapid generation of a high quality lead for transforming growth factor-beta (TGF-beta) type I receptor (ALK5).

Goldberg, Frederick W; Ward, Richard A; Powell, Steven J; Debreczeni, Judit E; Norman, Richard A; Roberts, Nicola J; Dishington, Allan P; Gingell, Helen J; Wickson, Kate F; Roberts, Andrew L.

J Med Chem ; 52(23): 7901-5, 2009 Dec 10.

Article in English | MEDLINE | ID: mdl-19736928

ABSTRACT

A novel class of 4-pyridinoxy-2-anilinopyridine-based TGF-beta type I receptor (also known as activin-like kinase 5 or ALK5) inhibitors is reported. The binding mode of this scaffold was successfully predicted by analyzing possible docked binding modes of literature inhibitors and novel synthetic ideas. Compounds such as 19 are potent ALK5 inhibitors with good physicochemical and pharmacokinetic properties and thus represent high quality leads for further optimization.

Subject(s)

Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyridines/chemistry , Pyridines/pharmacology , Receptors, Transforming Growth Factor beta/antagonists & inhibitors , Animals , Catalytic Domain , Cell Line, Tumor , Drug Discovery , Humans , Inhibitory Concentration 50 , Kinetics , Male , Models, Molecular , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/pharmacokinetics , Protein Serine-Threonine Kinases/chemistry , Protein Serine-Threonine Kinases/metabolism , Pyridines/metabolism , Pyridines/pharmacokinetics , Rats , Receptor, Transforming Growth Factor-beta Type I , Receptors, Transforming Growth Factor beta/chemistry , Receptors, Transforming Growth Factor beta/metabolism , Structure-Activity Relationship

ABSTRACT

Subject(s)

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