Property based optimization of δ-lactam HDAC inhibitors for metabolic stability.
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.
Yoon
Hong Chul
HC
Translational Research Center for Protein Function Control, Department of Biotechnology, Yonsei University, Seodaemun-gu, Seoul 120-749, Republic of Korea.
Choi
Eunhyun
E
Park
Jung Eun
JE
Cho
Misun
M
Seo
Jeong Jea
JJ
Oh
Soo Jin
SJ
Kang
Jong Soon
JS
Kim
Hwan Mook
HM
Park
Song-Kyu
SK
Lee
Kiho
K
Han
Gyoonhee
G
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
D056572:Histone Deacetylase Inhibitors; D007769:Lactams