Utilization of a nitrogen-sulfur nonbonding interaction in the design of new 2-aminothiazol-5-yl-pyrimidines as p38α MAP kinase inhibitors

Shuqun Lin, Stephen T. Wrobleski, John Hynes, Sidney Pitt, Rosemary Zhang, Yi Fan, Arthur M. Doweyko, Kevin F. Kish, John S. Sack, Mary F. Malley, Susan E. Kiefer, John A. Newitt, Murray McKinnon, James Trzaskos, Joel C. Barrish, John H. Dodd, Gary L. Schieven, Katerina Leftheris

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

The design, synthesis, and structure-activity relationships (SAR) of a series of 2-aminothiazol-5-yl-pyrimidines as novel p38α MAP kinase inhibitors are described. These efforts led to the identification of 41 as a potent p38α inhibitor that utilizes a unique nitrogen-sulfur intramolecular nonbonding interaction to stabilize the conformation required for binding to the p38α active site. X-ray crystallographic studies that confirm the proposed binding mode of this class of inhibitors in p38α and provide evidence for the proposed intramolecular nitrogen-sulfur interaction are discussed.

Original languageEnglish (US)
Pages (from-to)5864-5868
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume20
Issue number19
DOIs
StatePublished - Oct 1 2010

All Science Journal Classification (ASJC) codes

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

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