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]

Abstract

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-kappaB 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 critical for activity. If it was moved to the 6-position, the activity was lost. The 2-methyl analogue of 1 (81) showed comparable in vitro activity and improved Caco-2 permeability compared to 1.

Small Molecule Inhibitors Targeting Activator Protein 1 (AP-1)

“…111 However, the low aqueous solubility and high lipophilicity of 1 likely gave reason for the lack of poor oral activity in the animal models, consistent with its poor permeability in the gastrointestinal cell line, Caco-2 (apparent permeability coefficient P app = (11 ± 4) × 10 –7 cm/s). 112 …”

Synthesis and Antifungal Activity of N-(Substituted pyridinyl)-1-methyl(phenyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide Derivatives

“…Subsequently 4 and 8 were refluxed in SOCl 2 to give pyrazole acid chlorides 5 and 9 . Compounds 6a – l and 10a – k were then obtained by reaction of 5 or 9 with different substituted pyridylamines, respectively [17,18]. The 1 H-NMR, 13 C-NMR, IR and MS data and elemental analysis for the synthesized new compounds were consistent with assigned structures.…”

Synthesis, antiplasmodial activity and mechanistic studies of pyrimidine-5-carbonitrile and quinoline hybrids

“…Calcd. for C 28 H 28 ClN 7 O: C,65.49;H,5.45;N,19.10;Found: C,65.41;H,5.60;N,19.01. EIMS: m/z 514 (M þ H) þ .…”