The development of novel inhibitors of tumor necrosis factor-alpha (TNF-alpha) production based on substituted [5,5]-bicyclic pyrazolones.
Novel substituted [5,5]-bicyclic pyrzazolones are presented as inhibitors of tumor necrosis factor-alpha (TNF-alpha) production. Many of these compounds show low nanomolar activity against lipopolysaccaride (LPS)-induced TNF-alpha production in THP-1 cells. This class of molecules was co-crystallized with mutated p38, and several analogs showed good oral bioavailability in the rat. Oral activity of these compounds in the rat iodoacetate model for osteoarthritis is discussed.
Laufersweiler
Matthew J
MJ
Procter and Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason-Montgomery Rd, Mason, OH 45040, USA. laufersweiler.mj@pg.com
Brugel
Todd A
TA
Clark
Michael P
MP
Golebiowski
Adam
A
Bookland
Roger G
RG
Laughlin
Steven K
SK
Sabat
Mark P
MP
Townes
Jennifer A
JA
VanRens
John C
JC
De
Biswanath
B
Hsieh
Lily C
LC
Heitmeyer
Sandra A
SA
Juergens
Karen
K
Brown
Kimberly K
KK
Mekel
Marlene J
MJ
Walter
Richard L
RL
Janusz
Michael J
MJ
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D008070:Lipopolysaccharides / Q000494:pharmacology; D008958:Models, Molecular; D047069:Pyrazolones / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
D008070:Lipopolysaccharides; D047069:Pyrazolones; D014409:Tumor Necrosis Factor-alpha