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

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• 作者：Christopher D. Cox ; Paul J. Coleman ; Michael J. Breslin ; David B. Whitman ; Robert M. Garbaccio ; Mark E. Fraley ; Carolyn A. Buser ; Eileen S. Walsh ; Kelly Hamilton ; Michael D. Schaber ; Robert B. Lobell
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：July 24, 2008
• 年：2008
• 卷：51
• 期：14
• 页码：4239-4252
• 全文大小：359K
• 年卷期：v.51,no.14(July 24, 2008)
• ISSN：1520-4804

文摘

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 β-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.