Property-Based Optimization of Hydroxamate-Based 纬-Lactam HDAC Inhibitors to Improve Their Metabolic Stability and Pharmacokinetic Profiles

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• 作者：Eunhyun Choi ; Chulho Lee ; Misun Cho ; Jeong Jea Seo ; Jee Sun Yang ; Soo Jin Oh ; Kiho Lee ; Song-Kyu Park ; Hwan Mook Kim ; Ho Jeong Kwon ; Gyoonhee Han
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：December 13, 2012
• 年：2012
• 卷：55
• 期：23
• 页码：10766-10770
• 全文大小：227K
• 年卷期：v.55,no.23(December 13, 2012)
• ISSN：1520-4804

文摘

Hydroxamate-based HDAC inhibitors have promising anticancer activities but metabolic instability and poor pharmacokinetics leading to poor in vivo results. QSAR and PK studies of HDAC inhibitors showed that a 纬-lactam core and a modified cap group, including halo, alkyl, and alkoxy groups with various carbon chain linkers, improved HDAC inhibition and metabolic stability. The biological properties of the 纬-lactam HDAC inhibitors were evaluated; the compound designated 8f had potent anticancer activity and high oral bioavailability.