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-fluorin
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- 作者：Christopher D. Cox ; Michael J. Breslin ; David B. Whitman ; Paul J. Coleman ; Robert M. Garbaccio ; Mark E. Fraley ; Matthew M. Zrada ; Carolyn A. Buser ; Eileen S. Walsh ; Kelly Hamilton ; et al.
- 关键词：Pgp ; Antimitotics ; Multidrug-resistance
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2007
- 出版时间：15 May 2007
- 年：2007
- 卷：17
- 期：10
- 页码：2697-2702
- 全文大小：178 K
文摘
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 β-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.