Aurora Kinase Inhibitors Based on the Imidazo[1,2-a]pyrazine Core: Fluorine and Deuterium Incorporation Improve Oral Absorption and Exposure

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• 作者：Angela D. Kerekes ; Sara J. Esposite ; Ronald J. Doll ; Jayaram R. Tagat ; Tao Yu ; Yushi Xiao ; Yonglian Zhang ; Dan B. Prelusky ; Seema Tevar ; Kimberly Gray ; Gaby A. Terracina ; Suining Lee ; Jennifer Jones ; Ming Liu ; Andrea D. Basso ; Elizabeth B. Smith
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：January 13, 2011
• 年：2011
• 卷：54
• 期：1
• 页码：201-210
• 全文大小：957K
• 年卷期：v.54,no.1(January 13, 2011)
• ISSN：1520-4804

文摘

Aurora kinases are cell cycle regulated serine/threonine kinases that have been linked to cancer. Compound 1 was identified as a potent Aurora inhibitor but lacked oral bioavailability. Optimization of 1 led to the discovery of a series of fluoroamine and deuterated analogues, exemplified by compound 25, with an improved pharmacokinetic profile. We found that blocking oxidative metabolism at the benzylic position and decreasing the basicity of the amine are important to obtaining compounds with good biological profiles and oral bioavailability.