5-N-(3',5'-BIS(TRIFLUOROMETHYL)PHRNYL)-CARBOXAMIDE - A POTENT INHIBITOR OF NF-KAPPA-B-MEDIATED AND AP-1-MEDIATED GENE-EXPRESSION IDENTIFIEDUSING SOLUTION-PHASE COMBINATORIAL CHEMISTRY

Described is the identification of a novel series of compounds that bl ocks the activation of two key transcription factors, AP-1 and NF-kB. These transcription factors regulate the expression of several critica l proinflammatory proteins and cytokines and represent attractive targ ets for drug discovery. Through the use of high throughput screening a nd solution-phase parallel synthesis, inhibitors of both NF-kB and AP- 1 were identified. In subsequent testing, these compounds were also sh own to block both IL-2 and IL-8 levels in the same cells. One of the m ost potent compounds in this series, 28, was active in several animal models of inflammation and immunosuppression, thus validating the impo rtance of AP-1 and NF-kB as potential therapeutic targets. The synthes is and preliminary structure-activity relationships of these compounds is addressed.