期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 16, 期 12, 页码 3175-3179出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2006.03.040
关键词
kinesin spindle protein; anti-mitotic agents; structure-based design; dihydropyrazole
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.
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