2. Academic Validation
  3. Property-based optimization of hydroxamate-based γ-lactam HDAC inhibitors to improve their metabolic stability and pharmacokinetic profiles

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

Affiliation

  • 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.

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