Pyrazolo-pyrimidines: a novel heterocyclic scaffold for potent and selective p38 alpha inhibitors
Graduate School of Biomedical Sciences; Department of Pathology; Bristol-Myers Squibb Research and Development
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
Life Sciences | Medicine and Health Sciences
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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Citation: Bioorg Med Chem Lett. 2008 Apr 15;18(8):2652-7. Epub 2008 Mar 10. Link to article on publisher's site
Das, Jagabandhu; Moquin, Robert V.; Pitt, Sidney; Zhang, Rosemary F.; Shen, Ding Ren; McIntyre, Kim W.; Gillooly, Kathleen M.; Doweyko, Arthur M.; Sack, John S.; Zhang, Hongjian; Kiefer, Susan E.; Kish, Kevin; McKinnon, Murray; Barrish, Joel C.; Dodd, John H.; Schieven, Gary L.; and Leftheris, Katerina, "Pyrazolo-pyrimidines: a novel heterocyclic scaffold for potent and selective p38 alpha inhibitors" (2008). GSBS Student Publications. Paper 1469.