Enhanced selectivity profile of pyrazole-urea based DFG-out p38alpha inhibitors.
By targeting an extended region of the conventional 'DFG-out' pocket of p38alpha, while minimizing interactions with the specificity pocket and eliminating interactions with the adenine binding site, we are able to design and synthesize a number of pyrazole-urea based DFG-out p38alpha inhibitors with good potencies, and excellent selectivity.
Liu
Hu
H
Department of Chemistry, Cambridge South Laboratories, Pfizer Inc., 620 Memorial Drive, Cambridge, MA 02139, USA. hu.liu@pfizer.com
Kuhn
Cyrille
C
Feru
Frederic
F
Jacques
Suzanne L
SL
Deshmukh
Gayatri D
GD
Ye
Ping
P
Rennie
Glen R
GR
Johnson
Theresa
T
Kazmirski
Steven
S
Low
Simon
S
Coli
Rocco
R
Ding
Yuan-hua
YH
Cheng
Alan C
AC
Tecle
Haile
H
English
Jessie M
JM
Stanton
Robert
R
Wu
Joe C
JC
D000225:Adenine / Q000378:metabolism; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001665:Binding Sites; D006801:Humans; D008861:Microsomes / Q000378:metabolism; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010671:Phenylurea Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D048308:Mitogen-Activated Protein Kinase 14; D000225:Adenine