Synthesis and SAR of new pyrrolo[2,1-f][1,2,4]triazines as potent p38 alpha MAP kinase inhibitors.
A novel series of compounds based on the pyrrolo[2,1-f][1,2,4]triazine ring system have been identified as potent p38 alpha MAP kinase inhibitors. The synthesis, structure-activity relationships (SAR), and in vivo activity of selected analogs from this class of inhibitors are reported. Additional studies based on X-ray co-crystallography have revealed that one of the potent inhibitors from this series binds to the DFG-out conformation of the p38 alpha enzyme.
Wrobleski
Stephen T
ST
Department of Immunology Chemistry, Bristol-Myers Squibb, Princeton, NJ 08543-4000, USA. stephen.wrobleski@bms.com
Lin
Shuqun
S
Hynes
John
J
Wu
Hong
H
Pitt
Sidney
S
Shen
Ding Ren
DR
Zhang
Rosemary
R
Gillooly
Kathleen M
KM
Shuster
David J
DJ
McIntyre
Kim W
KW
Doweyko
Arthur M
AM
Kish
Kevin F
KF
Tredup
Jeffrey A
JA
Duke
Gerald J
GJ
Sack
John S
JS
McKinnon
Murray
M
Dodd
John
J
Barrish
Joel C
JC
Schieven
Gary L
GL
Leftheris
Katerina
K
D000577:Amides / Q000737:chemistry; D000818:Animals; D018360:Crystallography, X-Ray; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000577:Amides; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D014227:Triazines; D014409:Tumor Necrosis Factor-alpha; D048308:Mitogen-Activated Protein Kinase 14