Kinesin spindle protein (KSP) inhibitors.: 9.: Discovery of (2S)-4-(2,5-difluorophenyl)-N-[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide (MK-0731) for the treatment of taxane-refractory cancer

被引：140

作者：

Cox, Christopher D. ^{[1
]}

Coleman, Paul J. ^{[1
]}

Breslin, Michael J. ^{[1
]}

Whitman, David B. ^{[1
]}

Garbaccio, Robert M. ^{[1
]}

Fraley, Mark E. ^{[1
]}

Buser, Carolyn A. ^{[2
]}

Walsh, Eileen S. ^{[2
]}

Hamilton, Kelly ^{[2
]}

Schaber, Michael D. ^{[2
]}

Lobell, Robert B. ^{[2
]}

Tao, Weikang ^{[2
]}

Davide, Joseph P. ^{[2
]}

Diehl, Ronald E. ^{[2
]}

Abrams, Marc T. ^{[2
]}

South, Vicki J. ^{[2
]}

Huber, Hans E. ^{[2
]}

Torrent, Maricel ^{[3
]}

Prueksaritanont, Thomayant ^{[4
]}

Li, Chunze ^{[4
]}

Slaughter, Donald E. ^{[4
]}

Mahan, Elizabeth ^{[4
]}

Fernandez-Metzler, Carmen ^{[4
]}

Yan, Youwei ^{[5
]}

Kuo, Lawrence C. ^{[5
]}

Kohl, Nancy E. ^{[2
]}

Hartman, George D. ^{[1
]}

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

[3] Merck Res Labs, Dept Mol Syst, West Point, PA 19486 USA

[4] Merck Res Labs, Dept Drug Metab, West Point, PA 19486 USA

[5] Merck Res Labs, Dept Biol Struct, West Point, PA 19486 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2008年 / 51卷 / 14期

关键词：

D O I：

10.1021/jm800386y

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Inhibition of kinesin spindle protein (KSP) is a novel mechanism for treatment of cancer with the potential to overcome limitations associated with currently employed cytotoxic agents. Herein, we describe a C2-hydroxymethyl dihydropyrrole KSP inhibitor (11) that circumvents hERG channel binding and poor in vivo potency, issues that limited earlier compounds from our program. However, introduction of the C2-hydroxymethyl group caused 11 to be a substrate for cellular efflux by P-glycoprotein (Pgp). Utilizing knowledge garnered from previous KSP inhibitors, we found that beta-fluorination modulated the pK(a) of the piperidine nitrogen and reduced Pgp efflux, but the resulting compound (14) generated a toxic metabolite in vivo. Incorporation of fluorine in a strategic, metabolically benign position by synthesis of an N-methyl-3-fluoro-4-(aminomethyl)piperidine urea led to compound 30 that has an optimal in vitro and metabolic profile. Compound 30 (MK-0731) was recently studied in a phase I clinical trial in patients with taxane-refractory solid tumors.

引用

页码：4239 / 4252

页数：14

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