Inhibition of IKK-2 by 2-[(aminocarbonyl)amino]-5-acetylenyl-3-thiophenecarboxamides.
A series of 21 novel 2-[(aminocarbonyl)amino]-5-acetylenyl-3-thiophenecarboxamides were synthesized and evaluated for the inhibition of IKK-2. In spite of their often modest activity on the enzyme, six selected analogs showed significant inhibition of the production of inflammatory cytokine IL-8 in IL-1beta stimulated rheumatoid arthritis-derived synovial fibroblasts, demonstrating their potential usefulness as NF-kappaB regulators.
Bonafoux
Dominique
D
Department of Medicinal Chemistry, Pfizer Inc., St Louis, MO 63017, USA. bonafoux@biogenidec.com
Bonar
Sheri
S
Christine
Lori
L
Clare
Michael
M
Donnelly
Ann
A
Guzova
Julia
J
Kishore
Nandini
N
Lennon
Patrick
P
Libby
Adam
A
Mathialagan
Sumathy
S
McGhee
William
W
Rouw
Sharon
S
Sommers
Cindy
C
Tollefson
Michael
M
Tripp
Catherine
C
Weier
Richard
R
Wolfson
Serge
S
Min
Yao
Y
D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D051550:I-kappa B Kinase; D016209:Interleukin-8 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*
D016209:Interleukin-8; D013876:Thiophenes; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human