Discovery, Synthesis, and in Vivo Activity of a New Class of Pyrazoloquinazolines as Selective Inhibitors of Aurora B Kinase

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• 作者：Andrew A. Mortlock ; Kevin M. Foote ; Nicola M. Heron ; Fré ; dé ; ric H. Jung ; Georges Pasquet ; Jean-Jacques M. Lohmann ; Nicolas Warin ; Fabrice Renaud ; Chris De Savi ; Nicola J. Roberts ; Trevor J
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：May 3, 2007
• 年：2007
• 卷：50
• 期：9
• 页码：2213 - 2224
• 全文大小：181K
• 年卷期：v.50,no.9(May 3, 2007)
• ISSN：1520-4804

文摘

The Aurora kinases have been the subject of considerable interest as targets for the development of newanticancer agents. While evidence suggests inhibition of Aurora B kinase gives rise to the more pronouncedantiproliferative phenotype, the most clinically advanced agents reported to date typically inhibit both AuroraA and B. We have discovered a series of pyrazoloquinazolines, some of which show greater than 1000-foldselectivity for Aurora B over Aurora A kinase activity, in recombinant enzyme assays. These compoundshave been designed for parenteral administration and achieve high levels of solubility by virtue of theirability to be delivered as readily activated phosphate derivatives. The prodrugs are comprehensively convertedto the des-phosphate form in vivo, and the active species have advantageous pharmacokinetic propertiesand safety pharmacology profiles. The compounds display striking in vivo activity, and compound 5(AZD1152) has been selected for clinical evaluation and is currently in phase 1 clinical trials.