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

被引：65

作者：

Cox, CD

Torrent, M

Breslin, MJ

Mariano, BJ

Whitman, DB

Coleman, PJ

Buser, CA

Walsh, ES

Hamilton, K

Schaber, MD

Lobell, RB

Tao, WK

South, VJ

Kohl, NE

Yan, YW

Kuo, LC

Prueksaritanont, T

Slaughter, DE

Li, CZ

Mahan, E

Lu, B

Hartman, GD

机构：

[1] Merck Res Labs, Dept Med Chem, West Point, PA 19486 USA

[2] Merck Res Labs, Dept Mol Syst, West Point, PA 19486 USA

[3] Merck Res Labs, Dept Canc Res, West Point, PA 19486 USA

[4] Merck Res Labs, Dept Biol Struct, West Point, PA 19486 USA

[5] Merck Res Labs, Dept Drug Metab, West Point, PA 19486 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2006年 / 16卷 / 12期

关键词：

kinesin spindle protein; anti-mitotic agents; structure-based design; dihydropyrazole;

D O I：

10.1016/j.bmcl.2006.03.040

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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. (c) 2006 Elsevier Ltd. All rights reserved.

引用

页码：3175 / 3179

页数：5

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