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

✍ Scribed by 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

• Book ID: 104004837
• Publisher: Elsevier Science
• Year: 2010
• Tongue: English
• Weight: 205 KB
• Volume: 20
• Category: Article
• ISSN: 0960-894X
• DOI: 10.1016/j.bmcl.2010.08.117

✦ Synopsis

The novel d-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 d-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.