American Chemical Society
jm3009376_si_002.xls (97 kB)

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

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posted on 2016-02-20, 03:51 authored by 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
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 γ-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 γ-lactam HDAC inhibitors were evaluated; the compound designated 8f had potent anticancer activity and high oral bioavailability.