Synthesis and activity of new aryl- and heteroaryl-substituted pyrazole inhibitors of the transforming growth factor-beta type I receptor kinase domain.

J Scott Sawyer, Bryan D Anderson, Douglas W Beight, Robert M Campbell, Michael L Jones, David K Herron, John W Lampe, Jefferson R McCowan, William T McMillen, Nicholas Mort, Stephen Parsons, Edward C R Smith, Michal Vieth, Leonard C Weir, Lei Yan, Faming Zhang, Jonathan M Yingling

Index: J. Med. Chem. 46 , 3953-3956, (2003)

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Abstract

Pyrazole-based inhibitors of the transforming growth factor-beta type I receptor kinase domain (TbetaR-I) are described. Examination of the SAR in both enzyme- and cell-based in vitro assays resulted in the emergence of two subseries featuring differing selectivity versus p38 MAP kinase. A common binding mode at the active site has been established by successful cocrystallization and X-ray analysis of potent inhibitors with the TbetaR-I receptor kinase domain.