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

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.