Development of N-2,4-pyrimidine-N-phenyl-N'-phenyl ureas as inhibitors of tumor necrosis factor alpha (TNF-alpha) synthesis. Part 1.
A new class of tumor necrosis factor alpha (TNF-alpha) synthesis inhibitors based on an N-2,4-pyrimidine-N-phenyl-N'-phenyl urea scaffold is described. Many of these compounds showed low-nanomolar activity against lipopolysaccharide stimulated TNF-alpha production. X-ray co-crystallization studies with mutated p38alpha showed that these trisubstituted ureas interact with the ATP-binding pocket in a pseudo-bicyclic conformation brought about by the presence of an intramolecular hydrogen bonding interaction.
Brugel
Todd A
TA
Procter and Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason-Montgomery Rd., Mason, OH 45040, USA. brugel.ta@pg.com
Maier
Jennifer A
JA
Clark
Michael P
MP
Sabat
Mark
M
Golebiowski
Adam
A
Bookland
Roger G
RG
Laufersweiler
Matthew J
MJ
Laughlin
Steven K
SK
Vanrens
John C
JC
De
Biswanath
B
Hsieh
Lily C
LC
Mekel
Marlene J
MJ
Janusz
Michael J
MJ
D000255:Adenosine Triphosphate / Q000737:chemistry; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006860:Hydrogen Bonding; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D010671:Phenylurea Compounds / Q000737:chemistry* / Q000145:classification / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry* / Q000145:classification / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
D008070:Lipopolysaccharides; D010671:Phenylurea Compounds; D011743:Pyrimidines; D014409:Tumor Necrosis Factor-alpha; D000255:Adenosine Triphosphate