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

被引：19

作者：

Berger, Dan M. ^{[1
]}

Dutia, Minu ^{[1
]}

Powell, Dennis ^{[1
]}

Floyd, Middleton B. ^{[1
]}

Torres, Nancy ^{[1
]}

Mallon, Robert ^{[2
]}

Wojciechowicz, Donald ^{[2
]}

Kim, Steven ^{[2
]}

Feldberg, Larry ^{[2
]}

Collins, Karen ^{[2
]}

Chaudhary, Inder ^{[3
]}

机构：

[1] Wyeth Res, Chem & Screening Sci, Pearl River, NY 10965 USA

[2] Wyeth Res, Oncol, Pearl River, NY 10965 USA

[3] Wyeth Res, Drug Safety & Metab, Pearl River, NY 10965 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2008年 / 16卷 / 20期

关键词：

anticancer; MEK1; kinase inhibitor; 3-quinolinecarbonitriles;

D O I：

10.1016/j.bmc.2008.09.009

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 mu M of 5m. PK studies, as well as a xenograft and in vivo biomarker studies are described for 5m. (C) 2008 Elsevier Ltd. All rights reserved.

引用

页码：9202 / 9211

页数：10

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