2-Chloro-4-(trifluoromethyl)pyrimidine-5-N-(3',5'- bis(trifluoromethyl)phenyl)-carboxamide: a potent inhibitor of NF-kappa B- and AP-1-mediated gene expression identified using solution-phase combinatorial chemistry.
Described is the identification of a novel series of compounds that blocks the activation of two key transcription factors, AP-1 and NF-kappa B. These transcription factors regulate the expression of several critical proinflammatory proteins and cytokines and represent attractive targets for drug discovery. Through the use of high throughput screening and solution-phase parallel synthesis, inhibitors of both NF-kappa B and AP-1 were identified. In subsequent testing, these compounds were also shown to block both IL-2 and IL-8 levels in the same cells. One of the most potent compounds in this series, 28, was active in several animal models of inflammation and immunosuppression, thus validating the importance of AP-1 and NF-kappa B as potential therapeutic targets. The synthesis and preliminary structure-activity relationships of these compounds is addressed.
Sullivan
R W
RW
Department of Medicinal Chemistry, Signal Pharmaceuticals, Inc., San Diego, California 92121, USA.
Bigam
C G
CG
Erdman
P E
PE
Palanki
M S
MS
Anderson
D W
DW
Goldman
M E
ME
Ransone
L J
LJ
Suto
M J
MJ
D000199:Actins / Q000096:biosynthesis; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007165:Immunosuppression Therapy; D007249:Inflammation; D007376:Interleukin-2 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D019169:Jurkat Cells; D008156:Luciferases / Q000096:biosynthesis; D015394:Molecular Structure; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors*; D014162:Transfection
C110771:2-chloro-4-(trifluoromethyl)pyrimidine-5-N-(3',5'-bis(trifluoromethyl)pheyl)-carboxamide; D000199:Actins; D016207:Cytokines; D007376:Interleukin-2; D016209:Interleukin-8; D016328:NF-kappa B; D011743:Pyrimidines; D011993:Recombinant Fusion Proteins; D018808:Transcription Factor AP-1; D008156:Luciferases; D013755:Tetradecanoylphorbol Acetate