Property based optimization of δ-lactam HDAC inhibitors for metabolic stability

Hong Chul Yoon, Eunhyun Choi, Jung Eun Park, Misun Cho, Jeong Jea Seo, Soo Jin Oh, Jong Soon Kang, Hwan Mook Kim, Song Kyu Park, Kiho Lee, Gyoonhee Han

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)


The novel δ-lactam based HDAC inhibitor, KBH-A118 (3) shows a good HDAC enzyme and cancer cell growth inhibitory activities but has undesirable pharmacokinetics profiles because of instability in mouse liver microsome. To improve metabolic stability, various analogues were prepared with substituents on aromatic ring of cap group and various chain lengths between the cap group and δ-lactam core. The newly prepared analogues showed moderate to potent in vitro activities. Among them six compounds (8a, 8e, 8j, 8n, 8t, and 8v) were evaluated on mouse liver microsome assay and it turned out that the microsomal stabilities were dependent on lipophilicity and the number of the rotatable bonds. Finally, the animal pharmacokinetic profiles of 8e displayed improving oral exposure and oral bioavailability.

Original languageEnglish
Pages (from-to)6808-6811
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Issue number22
Publication statusPublished - 2010 Nov 15

Bibliographical note

Funding Information:
This research was supported by National Research Foundation ( 2009-0092966 ), Korea Research WCU grant ( R31-2008-000-10086-0 ) and Brain Korea 21 project, Republic of Korea.

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry


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