Synthesis and Activity of New Aryl- and
Heteroaryl-Substituted Pyrazole
Inhibitors of the Transforming Growth
Factor-β Type I Receptor Kinase Domain

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

doi:10.1021/jm0205705.s001

jm0205705_si_001.pdf (357.76 kB)

Synthesis and Activity of New Aryl- and Heteroaryl-Substituted Pyrazole Inhibitors of the Transforming Growth Factor-β Type I Receptor Kinase Domain

journal contribution

posted on 2003-08-12, 00:00 authored by 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

Pyrazole-based inhibitors of the transforming growth factor-β type I receptor kinase domain (TβR-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 TβR-I receptor kinase domain.