Two classes of p38alpha MAP kinase inhibitors having a common diphenylether core but exhibiting divergent binding modes.
Two new classes of diphenylether inhibitors of p38alpha MAP kinase are described. Both chemical classes are based on a common diphenylether core that is identified by simulated fragment annealing as one of the most favored chemotypes within a prominent hydrophobic pocket of the p38alpha ATP-binding site. In the fully elaborated molecules, the diphenylether moiety acts as an anchor occupying the deep pocket, while polar extensions make specific interactions with either the adenine binding site or the phosphate binding site of ATP. The synthesis, crystallographic analysis, and biological activity of these p38alpha inhibitors are discussed.
Michelotti
Enrique L
EL
Department of Chemistry, Locus Pharmaceuticals, Inc., Four Valley Square, 512 Township Line Rd, Blue Bell, PA 19422, USA.
Moffett
Kristofer K
KK
Nguyen
Duyan
D
Kelly
Martha J
MJ
Shetty
Rupa
R
Chai
Xiaomei
X
Northrop
Katrina
K
Namboodiri
Variketta
V
Campbell
Brandon
B
Flynn
Gary A
GA
Fujimoto
Ted
T
Hollinger
Frank P
FP
Bukhtiyarova
Marina
M
Springman
Eric B
EB
Karpusas
Michael
M
D001713:Biphenyl Compounds / Q000737:chemistry* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004987:Ethers / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000145:classification / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D001713:Biphenyl Compounds; D004987:Ethers; D047428:Protein Kinase Inhibitors; D048308:Mitogen-Activated Protein Kinase 14