Author/Authors :
Jagabandhu Das، نويسنده , , Robert V. Moquin، نويسنده , , Sidney Pitt، نويسنده , , Rosemary Zhang، نويسنده , , Ding Ren Shen، نويسنده , , Kim W. McIntyre، نويسنده , , Kathleen Gillooly، نويسنده , , Arthur M. Doweyko، نويسنده , , John S. Sack، نويسنده , , Hongjian Zhang، نويسنده , , Susan E. Kiefer، نويسنده , , Kevin Kish، نويسنده , , Murray McKinnon، نويسنده , , Joel C. Barrish، نويسنده , , John H. Dodd، نويسنده , , Gary L. Schieven، نويسنده , , Katerina Leftheris، نويسنده ,
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.
