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

  • J Med Chem. 2003 Sep 11;46(19):3953-6. doi: 10.1021/jm0205705.
J Scott Sawyer  1 ,  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
Affiliations
  • 1. Discovery Chemistry Research and Technology, The Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA. [email protected]
PMID: 12954047 DOI: 10.1021/jm0205705
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.