The development of monocyclic pyrazolone based cytokine synthesis inhibitors.
4-Aryl-5-pyrimidyl based cytokine synthesis inhibitors that contain a novel monocyclic, pyrazolone heterocyclic core are described. Many of these inhibitors showed low nanomolar activity against LPS-induced TNF-alpha production. One of the compounds (6e) was found to be efficacious in the rat iodoacetate (RIA) in vivo model of osteoarthritis. The X-ray crystal structure of a pyrazolone inhibitor cocrystallized with mutated p38 (mp38) is presented.
Golebiowski
Adam
A
Procter and Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason-Montgomery Rd, Mason, OH 45040, USA. golebiowski.a@pg.com
Townes
Jennifer A
JA
Laufersweiler
Matthew J
MJ
Brugel
Todd A
TA
Clark
Michael P
MP
Clark
Cynthia M
CM
Djung
Jane F
JF
Laughlin
Steven K
SK
Sabat
Mark P
MP
Bookland
Roger G
RG
VanRens
John C
JC
De
Biswanath
B
Hsieh
Lily C
LC
Janusz
Michael J
MJ
Walter
Richard L
RL
Webster
Mark E
ME
Mekel
Marlene J
MJ
D000818:Animals; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D010003:Osteoarthritis / Q000517:prevention & control; D047069:Pyrazolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
D016207:Cytokines; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D047069:Pyrazolones; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases