Discovery and characterization of the N-phenyl-N'-naphthylurea class of p38 kinase inhibitors.
An effort aimed at exploring structural diversity in the N-pyrazole-N'-naphthylurea class of p38 kinase inhibitors led to the synthesis and characterization of N-phenyl-N'-naphthylureas. Examples of these compounds displayed excellent inhibition of TNF-alpha production in vitro, as well as efficacy in a mouse model of lipopolysaccharide induced endotoxemia. In addition, perspective is provided on the role of a sulfonamide functionality in defining inhibitor potency.
Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceutical, Inc., 900 Ridgebury Road, Ridgefield, CT 06877, USA.
Pier F
PF
Cirillo
Eugene R
ER
Hickey
Neil
N
Moss
Steffen
S
Breitfelder
Raj
R
Betageri
Tazmeen
T
Fadra
Faith
F
Gaenzler
Thomas
T
Gilmore
Daniel R
DR
Goldberg
Victor
V
Kamhi
Thomas
T
Kirrane
Rachel R
RR
Kroe
Jeffrey
J
Madwed
Monica
M
Moriak
Matthew
M
Netherton
Christopher A
CA
Pargellis
Usha R
UR
Patel
Kevin C
KC
Qian
Rajiv
R
Sharma
Sanxing
S
Sun
Alan
A
Swinamer
Carol
C
Torcellini
Hidenori
H
Takahashi
Michele
M
Tsang
Zhaoming
Z
Xiong
D015081:2-Naphthylamine / Q000031:analogs & derivatives* / Q000737:chemistry; D000818:Animals; D002625:Chemistry, Organic / Q000379:methods; D002626:Chemistry, Pharmaceutical / Q000379:methods; D018360:Crystallography, X-Ray / Q000379:methods; D015195:Drug Design; D020128:Inhibitory Concentration 50; D008070:Lipopolysaccharides / Q000378:metabolism; D051379:Mice; D008956:Models, Chemical; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D008070:Lipopolysaccharides; D047428:Protein Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; C092587:di-2-naphthylurea; D014508:Urea; D015081:2-Naphthylamine; D048051:p38 Mitogen-Activated Protein Kinases