title: Property-based optimization of hydroxamate-based γ-lactam HDAC inhibitors to improve their metabolic stability and pharmacokinetic profiles.
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.
authors.affiliation: Severance Integrative Research Institute for Cerebral & Cardiovascular Disease, Yonsei University Health System, 250 Seongsanno, Seodaemun-Gu, Seoul 120-752, Republic of Korea.
authors.forename: Eunhyun
authors.initials: E
authors.lastname: Choi
authors.forename: Chulho
authors.initials: C
authors.lastname: Lee
authors.forename: Misun
authors.initials: M
authors.lastname: Cho
authors.forename: Jeong Jea
authors.initials: JJ
authors.lastname: Seo
authors.forename: Jee Sun
authors.initials: JS
authors.lastname: Yang
authors.forename: Soo Jin
authors.initials: SJ
authors.lastname: Oh
authors.forename: Kiho
authors.initials: K
authors.lastname: Lee
authors.forename: Song-Kyu
authors.initials: SK
authors.lastname: Park
authors.forename: Hwan Mook
authors.initials: HM
authors.lastname: Kim
authors.forename: Ho Jeong
authors.initials: HJ
authors.lastname: Kwon
authors.forename: Gyoonhee
authors.initials: G
authors.lastname: Han
mesh_terms: D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000737:chemistry*; D007769:Lactams / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007769:Lactams