4-Anilino-7-alkenylquinoline-3-carbonitriles as potent MEK1 kinase inhibitors

A series of substituted 7-alkenyl 4[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)]anilino-3-quinolinecarbonitrile analogs were synthesized and evaluated as MEK1 kinase inhibitors. The synthetic details, structure–activity relationships, biological activity, and selected oral exposure studies of these analogs are described. From these studies, compound 5m was chosen as a strong candidate for further evaluation. The selectivity of 5m was ascertained against a panel of 17 kinases, where activity was observed against EGFR, Src, Lyn, and IR kinases. Western blot studies in WM-266 cells demonstrated that 5m inhibited phosphorylation of ERK, while additional kinase pathways tested showed no inhibition at up to 10 μM of 5m. PK studies, as well as a xenograft and in vivo biomarker studies are described for 5m.

A series of 7-alkenyl substituted 4-anilino-3-quinolinecarbonitriles were prepared and evaluated as MEK1 kinase inhibitors. One analog (R = H, NR1R2 = N-ethylpiperazine, n = 2) was active in an H358 (lung) xenograft study when dosed orally.Figure optionsDownload as PowerPoint slide