Kinesin spindle protein (KSP) inhibitors. Part 4: Structure-based design of 5-alkylamino-3,5-diaryl-4,5-dihydropyrazoles as potent, water-soluble inhibitors of the mitotic kinesin KSP
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- 作者：Christopher D. Cox ; Maricel Torrent ; Michael J. Breslin ; Brenda J. Mariano ; David B. Whitman ; Paul J. Coleman ; Carolyn A. Buser ; Eileen S. Walsh ; Kelly Hamilton ; Michael D. Schaber et al.
- 关键词：Kinesin spindle protein ; Anti-mitotic agents ; Structure-based design ; Dihydropyrazole
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2006
- 出版时间：15 June 2006
- 年：2006
- 卷：16
- 期：12
- 页码：3175-3179
- 全文大小：313 K
文摘
Molecular modeling in combination with X-ray crystallographic information was employed to identify a region of the kinesin spindle protein (KSP) binding site not fully utilized by our first generation inhibitors. We discovered that by appending a propylamine substituent at the C5 carbon of a dihydropyrazole core, we could effectively fill this unoccupied region of space and engage in a hydrogen-bonding interaction with the enzyme backbone. This change led to a second generation compound with increased potency, a 400-fold enhancement in aqueous solubility at pH 4, and improved dog pharmacokinetics relative to the first generation compound.