Kinesin spindle protein (KSP) inhibitors. Part 3: Synthesis and evaluation of phenolic 2,4-diaryl-2,5-dihydropyrroles with reduced hERG binding and employment of a phosphate prodrug strategy for aqueo
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- 作者：Robert M. Garbaccio ; Mark E. Fraley ; Edward S. Tasber ; Christy M. Olson ; William F. Hoffman ; Kenneth L. Arrington ; Maricel Torrent ; Carolyn A. Buser ; Eileen S. Walsh ; Kelly Hamilton et al.
- 关键词：KSP ; Kinesin spindle protein ; Kinesin ; hERG ; Phosphate prodrug ; Cancer ; Antimitotic ; Dihydropyrrole ; Phenol
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2006
- 出版时间：1 April 2006
- 年：2006
- 卷：16
- 期：7
- 页码：1780-1783
- 全文大小：136 K
文摘
2,4-Diaryl-2,5-dihydropyrroles have been discovered to be novel, potent and water-soluble inhibitors of KSP, an emerging therapeutic target for the treatment of cancer. A potential concern for these basic KSP inhibitors (1 and 2) was hERG binding that can be minimized by incorporation of a potency-enhancing C2 phenol combined with neutral N1 side chains. Aqueous solubility was restored to these, and other, non-basic inhibitors, through a phosphate prodrug strategy.