Kinesin spindle protein (KSP) inhibitors. Part 7: Design and synthesis of 3,3-disubstituted dihydropyrazolobenzoxazines as potent inhibitors of the mitotic kinesin KSP
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- 作者：Robert M. Garbaccio ; Edward S. Tasber ; Lou Anne Neilson ; Paul J. Coleman ; Mark E. Fraley ; Christy Olson ; Jeff Bergman ; Maricel Torrent ; Carolyn A. Buser ; Keith Rickert ; Eileen S. Walsh ; Kelly Hamilton
- 关键词：KSP inhibitors ; Anti-mitotics ; Multidrug-resistance ; Pgp ; hERG ; Kinesins ; Pyrazolobenzoxazines ; [3+2] Cycloaddition ; Quaternary center ; Kinesin spindle protein ; Cancer
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2007
- 出版时间：15 October 2007
- 年：2007
- 卷：17
- 期：20
- 页码：5671-5676
- 全文大小：185 K
文摘
Observations from two structurally related series of KSP inhibitors led to the proposal and discovery of dihydropyrazolobenzoxazines that possess ideal properties for cancer drug development. The synthesis and characterization of this class of inhibitors along with relevant pharmacokinetic and in vivo data are presented. The synthesis is highlighted by a key [3+2] cycloaddition to form the pyrazolobenzoxazine core followed by diastereospecific installation of a quaternary center.