Inhibitors of NF-κB and AP-1 Gene Expression: SAR Studies on the Pyrimidine Portion of 2-Chloro-4-trifluoromethylpyrimidine-5-[N-(3‘,5‘-bis(trifluoromethyl)phenyl)carboxamide]

We investigated the structure−activity relationship studies of N-[3,5-bis(trifluoromethyl)phenyl][2-chloro-4-(trifluoromethyl)pyrimidin-5-yl]carboxamide (1), an inhibitor of transcription mediated by both NF-κB and AP-1 transcription factors, with the goal of improving its potential oral bioavailability. Compounds were examined for cell-based activity, were fit to Lipinski's rule of 5, and were examined for potential gastrointestinal permeability using the intestinal epithelial cell line, Caco-2. Selected groups were substituted at the 2-, 4-, and 5-positions of the pyrimidine ring using solution-phase combinatorial methodology. The introduction of a fluorine in the place of 2-chlorine of 1 resulted in a compound with comparable activity. However, other substitutions at the 2-position resulted in a loss of activity. The trifluoromethyl group at the 4-position could be replaced with a methyl, ethyl, chlorine, or phenyl without a substantial loss of activity. The carboxamide group at the 5-position is criti...