Title
Pyrazolo-pyrimidines: a novel heterocyclic scaffold for potent and selective p38 alpha inhibitors
UMMS Affiliation
Graduate School of Biomedical Sciences; Department of Pathology; Bristol-Myers Squibb Research and Development
Date
3-25-2008
Document Type
Article
Medical Subject Headings
Crystallography, X-Ray; Humans; Models, Molecular; Molecular Structure; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Structure-Activity Relationship; p38 Mitogen-Activated Protein Kinases; inhibitors
Disciplines
Life Sciences | Medicine and Health Sciences
Abstract
The synthesis and structure-activity relationships (SAR) of p38 alpha 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 p38 alpha MAP kinase with excellent cellular potency toward the inhibition of TNFalpha production. Compound 2x was highly efficacious in vivo in inhibiting TNFalpha production in an acute murine model of TNFalpha production. X-ray co-crystallography of a pyrazolo-pyrimidine analog 2b bound to unphosphorylated p38 alpha is also disclosed.
Rights and Permissions
Citation: Bioorg Med Chem Lett. 2008 Apr 15;18(8):2652-7. Epub 2008 Mar 10. Link to article on publisher's site