title: Property based optimization of δ-lactam HDAC inhibitors for metabolic stability.
abstract: 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.
authors.affiliation: Translational Research Center for Protein Function Control, Department of Biotechnology, Yonsei University, Seodaemun-gu, Seoul 120-749, Republic of Korea.
authors.forename: Hong Chul
authors.initials: HC
authors.lastname: Yoon
authors.forename: Eunhyun
authors.initials: E
authors.lastname: Choi
authors.forename: Jung Eun
authors.initials: JE
authors.lastname: Park
authors.forename: Misun
authors.initials: M
authors.lastname: Cho
authors.forename: Jeong Jea
authors.initials: JJ
authors.lastname: Seo
authors.forename: Soo Jin
authors.initials: SJ
authors.lastname: Oh
authors.forename: Jong Soon
authors.initials: JS
authors.lastname: Kang
authors.forename: Hwan Mook
authors.initials: HM
authors.lastname: Kim
authors.forename: Song-Kyu
authors.initials: SK
authors.lastname: Park
authors.forename: Kiho
authors.initials: K
authors.lastname: Lee
authors.forename: Gyoonhee
authors.initials: G
authors.lastname: Han
mesh_terms: D000818:Animals; D001682:Biological Availability; D045744:Cell Line, Tumor; D056572:Histone Deacetylase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007769:Lactams / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice
chemical_list: D056572:Histone Deacetylase Inhibitors; D007769:Lactams