Pyrazolo-pyrimidines: A novel heterocyclic scaffold for potent and selective p38α inhibitors

Jagabandhu Das, Robert V. Moquin, Sidney Pitt, Rosemary Zhang, Ding Ren Shen, Kim W. McIntyre, Kathleen Gillooly, Arthur M. Doweyko, John S. Sack, Hongjian Zhang, Susan E. Kiefer, Kevin Kish, Murray McKinnon, Joel C. Barrish, John Harold Dodd, Gary L. Schieven, Katerina Leftheris

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

The synthesis and structure-activity relationships (SAR) of p38α MAP kinase inhibitors based on a pyrazolo-pyrimidine scaffold are described. These studies led to the identification of compound 2x as a potent and selective inhibitor of p38α MAP kinase with excellent cellular potency toward the inhibition of TNFα production. Compound 2x was highly efficacious in vivo in inhibiting TNFα production in an acute murine model of TNFα production. X-ray co-crystallography of a pyrazolo-pyrimidine analog 2b bound to unphosphorylated p38α is also disclosed.

Original languageEnglish (US)
Pages (from-to)2652-2657
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume18
Issue number8
DOIs
Publication statusPublished - Apr 15 2008

    Fingerprint

All Science Journal Classification (ASJC) codes

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

Cite this

Das, J., Moquin, R. V., Pitt, S., Zhang, R., Shen, D. R., McIntyre, K. W., ... Leftheris, K. (2008). Pyrazolo-pyrimidines: A novel heterocyclic scaffold for potent and selective p38α inhibitors. Bioorganic and Medicinal Chemistry Letters, 18(8), 2652-2657. https://doi.org/10.1016/j.bmcl.2008.03.019