Pyrazolo-pyrimidines: a novel heterocyclic scaffold for potent and selective p38 alpha inhibitors.

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Das J, Moquin RV, Pitt S, Zhang R, Shen DR, McIntyre KW, Gillooly K, Doweyko AM, Sack JS, Zhang H, Kiefer SE, Kish K, McKinnon M, Barrish JC, Dodd JH, Schieven GL, Leftheris K

Pyrazolo-pyrimidines: a novel heterocyclic scaffold for potent and selective p38 alpha inhibitors.

Bioorg Med Chem Lett. 2008 Apr 15;18(8):2652-7. doi: 10.1016/j.bmcl.2008.03.019. Epub 2008 Mar 10.

PubMed ID

18359226 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
N,4-dimethyl-3-[(1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]benzamide	Mitogen-activated protein kinase 14	IC 50 (nM)	10	N/A	N/A	Details