Synthesis and activity of new aryl- and heteroaryl-substituted 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole inhibitors of the transforming growth factor-β type I receptor kinase domain

J. Scott Sawyer, Douglas W. Beight, Karen S. Britt, Bryan D. Anderson, Robert M. Campbell, Theodore Goodson, David K. Herron, Hong Yu Li, William T. McMillen, Nicholas Mort, Stephen Parsons, Edward C.R. Smith, Jill R. Wagner, Lei Yan, Faming Zhang, Jonathan M. Yingling

Research output: Contribution to journalArticlepeer-review

120 Scopus citations

Abstract

We have expanded our previously reported series of pyrazole-based inhibitors of the TGF-β type I receptor kinase domain (TβR-I) to now include new 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole analogues. Limited examination of the SAR of this new series in both enzyme and cell based in vitro assays has revealed selectivity differences with respect to p38 MAP kinase (p38 MAPK) depending on the nature of the 'warhead' group on the dihydropyrrolopyrazole ring. As with our original pyrazole series, phenyl substituents tended to show greater selectivity against p38 MAPK than those comprised of the quinoline-4-yl moiety. We have also achieved co-crystallization and X-ray analysis of compounds 3 and 15, two potent examples of this new series, with the TβR-I receptor kinase domain.

Original languageEnglish (US)
Pages (from-to)3581-3584
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume14
Issue number13
DOIs
StatePublished - Jul 5 2004

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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