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

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Abstract

The synthesis and structure–activity relationships (SAR) of p38α 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 p38α MAP kinase with excellent cellular potency toward the inhibition of TNFα production. Compound 2x was highly efficacious in vivo in inhibiting TNFα production in an acute murine model of TNFα production. X-ray co-crystallography of a pyrazolo-pyrimidine analog 2b bound to unphosphorylated p38α is also disclosed.

Graphical abstract

The synthesis and structure–activity relationships (SAR) of p38α 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 p38α MAP kinase with excellent cellular potency toward the inhibition of TNFα production. Compound 2x was highly efficacious in vivo in inhibiting TNFα production in an acute murine model of TNF production. X-ray co-crystallography of a pyrazolo-pyrimidine analog 2b bound to unphosphorylated p38α is also disclosed.

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    Several compounds as xanthene attached amino acids [15], piperazine-1-carbothioamide chitosan silver nanoparticles [16], dihydrazones [17], coumarins [18], benzo[d]thiazoles [19] and sulfur containing motifs [20] have exhibited anti-inflammatory activities. The anti-inflammatory properties of pyrazolo[3,4-d]pyrimidine compounds as potential inhibitors of cyclooxygenase (COX) [21] and p38α isoenzymes [22,23] are well known and gaining more interest. Traditional non-steroidal anti-inflammatory drugs (NSAIDs) are still the most commonly prescribed medications to alleviate acute and chronic inflammation, pain and fever.

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