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 microM of 5 m. PK studies, as well as a xenograft and in vivo biomarker studies are described for 5m.
Berger
Dan M
DM
Chemical & Screening Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, USA. bergerd@wyeth.com
Dutia
Minu
M
Powell
Dennis
D
Floyd
Middleton B
MB
Torres
Nancy
N
Mallon
Robert
R
Wojciechowicz
Donald
D
Kim
Steven
S
Feldberg
Larry
L
Collins
Karen
K
Chaudhary
Inder
I
D000475:Alkenes / Q000737:chemistry*; D000814:Aniline Compounds / Q000737:chemistry*; D000818:Animals; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D007546:Isoquinolines / Q000737:chemistry; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D009369:Neoplasms / Q000201:enzymology; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D023041:Xenograft Model Antitumor Assays
D000475:Alkenes; D000814:Aniline Compounds; D007546:Isoquinolines; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D048369:MAP Kinase Kinase 1; C023650:aniline