Design and Synthesis of Orally Bioavailable Aminopyrrolidinone Histone Deacetylase 6 Inhibitors

• DOI: 10.1021/jm502011f
• Publication Date: 2015-03-03T20:08:41Z
• Authors: Xianfeng Lin; Wenming Chen; Zongxing Qiu; Lei Guo; Wei Zhu; Wentao Li; Zhanguo Wang; Weixing Zhang; Zhenshan Zhang; Yiping Rong; Meifang Zhang; Lingjie Yu; Sheng Zhong; Rong Zhao; Xihan Wu; Jason C. Wong; Guozhi Tang
• Keywords: Histone deacetylase inhibitor; Orally active

Histone deacetylase 6 (HDAC6) removes the acetyl group from lysine residues in a number of non-histone substrates and plays important roles microtubule dynamics chaperone activities. There is growing interest identifying HDAC6-selective inhibitors as chemical biology tools ultimately new therapeutic agents. Herein we report design, synthesis, phenotypic screening novel class 3-aminopyrrolidinone-based hydroxamic acids HDAC6 inhibitors. In particular, α-methyl-substituted enantiomer 33 (3-S) showed significant in-cell tubulin acetylation (Tub-Ac) with an EC50 0.30 μM but limited impact on p21 levels at various concentrations. enzyme inhibition assays, demonstrated high selectivity for IC50 0.017 indexes 10 against HDAC8 over 4000 HDAC1-3 isoforms. Moreover, has suitable drug metabolism pharmacokinetics properties compared other acid-based HDAC inhibitors, warranting further biological studies development selective inhibitor.