Development of orally bioavailable bicyclic pyrazolones as inhibitors of tumor necrosis factor-alpha production.
2-Aryl-3-pyrimidinyl based tumor necrosis factor-alpha (TNF-alpha) inhibitors, which contain a novel bicyclic pyrazolone core, are described. Many showed low-nanomolar activity against lipopolysaccharide-induced TNF-alpha production in monocytic cells. Secondary screening data are presented for the pyrimidinyl bicyclic pyrazolones. Several of these analogues showed good oral bioavailability in rat and efficacy in the rat iodoacetate in vivo model.
Clark
Michael P
MP
Health Care Research Center, Procter and Gamble Pharmaceuticals, 8700 Mason-Montgomery Road, Mason, Ohio 45040, USA. clark.mp@pg.com
Laughlin
Steven K
SK
Laufersweiler
Matthew J
MJ
Bookland
Roger G
RG
Brugel
Todd A
TA
Golebiowski
Adam
A
Sabat
Mark P
MP
Townes
Jennifer A
JA
VanRens
John C
JC
Djung
Jane F
JF
Natchus
Michael G
MG
De
Biswanath
B
Hsieh
Lily C
LC
Xu
Susan C
SC
Walter
Rick L
RL
Mekel
Marlene J
MJ
Heitmeyer
Sandra A
SA
Brown
Kimberly K
KK
Juergens
Karen
K
Taiwo
Yetunde O
YO
Janusz
Michael J
MJ
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D006801:Humans; D066298:In Vitro Techniques; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D010770:Phosphotransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
D011720:Pyrazoles; D011743:Pyrimidines; D014409:Tumor Necrosis Factor-alpha; D010770:Phosphotransferases