Kinesin spindle protein (KSP) inhibitors.: Part V:: Discovery of 2-propylamino-2,4-diaryl-2,5-dihydropyrroles as potent, water-soluble KSP inhibitors, and modulation of their basicity by β-fluorination to overcome cellular efflux by P-glycoprotein

被引：49

作者：

Cox, Christopher D.

Breslin, Michael J.

Whitman, David B.

Coleman, Paul J.

Garbaccio, Robert M.

Fraley, Mark E.

Zrada, Matthew M.

Buser, Carolyn A.

Walsh, Eileen S.

Hamilton, Kelly

Lobell, Robert B.

Tao, Weikang

Abrams, Marc T.

South, Vicki J.

Huber, Hans E.

Kohl, Nancy E.

Hartman, George D.

机构：

[1] Merck Res Labs, Dept Med Chem, West Point, PA 19486 USA

[2] Merck Res Labs, Dept Canc Res, West Point, PA 19486 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2007年 / 17卷 / 10期

关键词：

Pgp; antimitotics; multidrug-resistance;

D O I：

10.1016/j.bmcl.2007.03.006

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Installation of a C2-aminopropyl side chain to the 2,4-diaryl-2,5-dihydropyrrole series of kinesin spindle protein (KSP) inhibitors results in potent, water soluble compounds, but the aminopropyl group induces susceptibility to cellular efflux by P-glycoprotein (Pgp). We show that by carefully modulating the basicity of the amino group by beta-fluorination, this series of inhibitors maintains potency against KSP and has greatly improved efficacy in a Pgp-overexpressing cell line. The discovery that cellular efflux by Pgp can be overcome by carefully modulating the basicity of an amine may be of general use to medicinal chemists attempting to transform leading compounds into cancer cell- or CNS-penetrant drugs. (c) 2007 Elsevier Ltd. All rights reserved.

引用

页码：2697 / 2702

页数：6

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