title: Pyrazolo-pyrimidines: a novel heterocyclic scaffold for potent and selective p38 alpha inhibitors.
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.
authors: Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543-4000, USA. jagabandhu.das@bms.com
authors: Jagabandhu
authors: J
authors: Das
authors: Robert V
authors: RV
authors: Moquin
authors: Sidney
authors: S
authors: Pitt
authors: Rosemary
authors: R
authors: Zhang
authors: Ding Ren
authors: DR
authors: Shen
authors: Kim W
authors: KW
authors: McIntyre
authors: Kathleen
authors: K
authors: Gillooly
authors: Arthur M
authors: AM
authors: Doweyko
authors: John S
authors: JS
authors: Sack
authors: Hongjian
authors: H
authors: Zhang
authors: Susan E
authors: SE
authors: Kiefer
authors: Kevin
authors: K
authors: Kish
authors: Murray
authors: M
authors: McKinnon
authors: Joel C
authors: JC
authors: Barrish
authors: John H
authors: JH
authors: Dodd
authors: Gary L
authors: GL
authors: Schieven
authors: Katerina
authors: K
authors: Leftheris
mesh_terms: 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*
chemical_list: D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D048051:p38 Mitogen-Activated Protein Kinases; C030986:pyrimidine