Synthesis and pharmacological characterization of a potent, orally active p38 kinase inhibitor.
Inhibitors of the MAP kinase p38 provide a novel approach for the treatment of osteoporosis, inflammatory disorders, and cancer. We have identified N-(3-tert-butyl-1-methyl-5-pyrazolyl)-N'-(4-(4-pyridinylmethyl)phenyl)urea as a potent and selective p38 kinase inhibitor in biochemical and cellular assays. This compound is orally active in two acute models of cytokine release (TNF-induced IL-6 and LPS-induced TNF) and a chronic model of arthritis (20-day murine collagen-induced arthritis).
Dumas
Jacques
J
Department of Chemistry Research, Bayer Research Center, 400 Morgan Lane, West Haven, CT 06516, USA. jacques.dumas.b@bayer.com
Hatoum-Mokdad
Holia
H
Sibley
Robert N
RN
Smith
Roger A
RA
Scott
William J
WJ
Khire
Uday
U
Lee
Wendy
W
Wood
Jill
J
Wolanin
Donald
D
Cooley
Jeffrey
J
Bankston
Donald
D
Redman
Aniko M
AM
Schoenleber
Robert
R
Caringal
Yolanda
Y
Gunn
David
D
Romero
Romulo
R
Osterhout
Martin
M
Paulsen
Holger
H
Housley
Timothy J
TJ
Wilhelm
Scott M
SM
Pirro
John
J
Chien
Du-Shieng
DS
Ranges
Gerald E
GE
Shrikhande
Alka
A
Muzsi
Andrew
A
Bortolon
Elizabeth
E
Wakefield
Jean
J
Gianpaolo Ostravage
Cynthia
C
Bhargava
Ajay
A
Chau
Thuy
T
D000284:Administration, Oral; D000818:Animals; D001168:Arthritis / Q000188:drug therapy; D016207:Cytokines / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D014508:Urea / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D048051:p38 Mitogen-Activated Protein Kinases
D016207:Cytokines; D004791:Enzyme Inhibitors; C468807:N-(3-tert-butyl-1-methyl-5-pyrazolyl)-N'-(4-(4-pyridinylmethyl)phenyl)urea; D014508:Urea; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases