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.

基于羟基氨酯的组蛋白脱乙酰化酶（HDAC）抑制剂展现出令人期待的抗癌活性，然而其代谢不稳定性以及不良的药代动力学特性导致体内实验结果不尽如人意。针对HDAC抑制剂的定量构效关系（QSAR）和药代动力学（PK）研究揭示了γ-内酰胺核心以及经过修饰的帽子基团，包括卤素、烷基和烷氧基等不同碳链连接基团，能够提升HDAC抑制效果及代谢稳定性。对γ-内酰胺HDAC抑制剂的生物特性进行了评估；标记为8f的化合物展现出显著的抗癌活性和较高的口服生物利用度。