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.
Cirillo
Pier F
PF
Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceutical, Inc., 900 Ridgebury Road, Ridgefield, CT 06877, USA.
Hickey
Eugene R
ER
Moss
Neil
N
Breitfelder
Steffen
S
Betageri
Raj
R
Fadra
Tazmeen
T
Gaenzler
Faith
F
Gilmore
Thomas
T
Goldberg
Daniel R
DR
Kamhi
Victor
V
Kirrane
Thomas
T
Kroe
Rachel R
RR
Madwed
Jeffrey
J
Moriak
Monica
M
Netherton
Matthew
M
Pargellis
Christopher A
CA
Patel
Usha R
UR
Qian
Kevin C
KC
Sharma
Rajiv
R
Sun
Sanxing
S
Swinamer
Alan
A
Torcellini
Carol
C
Takahashi
Hidenori
H
Tsang
Michele
M
Xiong
Zhaoming
Z
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