Pyrazolo-pyrimidines: a novel heterocyclic scaffold for potent and selective p38 alpha inhibitors.
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.
Das
Jagabandhu
J
Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543-4000, USA. jagabandhu.das@bms.com
Moquin
Robert V
RV
Pitt
Sidney
S
Zhang
Rosemary
R
Shen
Ding Ren
DR
McIntyre
Kim W
KW
Gillooly
Kathleen
K
Doweyko
Arthur M
AM
Sack
John S
JS
Zhang
Hongjian
H
Kiefer
Susan E
SE
Kish
Kevin
K
McKinnon
Murray
M
Barrish
Joel C
JC
Dodd
John H
JH
Schieven
Gary L
GL
Leftheris
Katerina
K
D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011720:Pyrazoles / Q000737:chemistry*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*
D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D048051:p38 Mitogen-Activated Protein Kinases; C030986:pyrimidine