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

Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543-4000, USA.
Bioorganic & medicinal chemistry letters (Impact Factor: 2.42). 05/2008; 18(8):2652-7. DOI: 10.1016/j.bmcl.2008.03.019
Source: PubMed


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.

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