Property-based optimization of hydroxamate-based γ-lactam HDAC inhibitors to improve their metabolic stability and pharmacokinetic profiles

  • J Med Chem. 2012 Dec 13;55(23):10766-70. doi: 10.1021/jm3009376.
Eunhyun Choi  1 ,  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
Affiliations
  • 1. Severance Integrative Research Institute for Cerebral & Cardiovascular Disease, Yonsei University Health System, 250 Seongsanno, Seodaemun-Gu, Seoul 120-752, Republic of Korea.
PMID: 23163332 DOI: 10.1021/jm3009376
Abstract

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.