Discovery and Extensive in Vitro Evaluations of NK-HDAC-1: A Chiral Histone Deacetylase Inhibitor as a Promising Lead

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• 作者：Jingli Hou ; Zhonghua Li ; Qinghong Fang ; Congran Feng ; Hanwen Zhang ; Weikang Guo ; Huihui Wang ; Guoxian Gu ; Yinping Tian ; Pi Liu ; Ruihua Liu ; Jianping Lin ; Yi-kang Shi ; Zheng Yin ; Jie Shen ; Peng George Wang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：April 12, 2012
• 年：2012
• 卷：55
• 期：7
• 页码：3066-3075
• 全文大小：526K
• 年卷期：v.55,no.7(April 12, 2012)
• ISSN：1520-4804

文摘

Herein, further SAR studies of lead compound NSC746457 (Shen, J.; Woodward,R.; Kedenburg,J. P.; Liu, X. W.; Chen, M.; Fang, L. Y.; Sun; D. X.; Wang. P. G. J. Med. Chem. 2008, 51, 7417鈭?427) were performed, including the replacement of the trans-styryl moiety with a 2-substituted benzo-hetero aromatic ring and the introduction of a substituent onto the central methylene carbon. A promising chiral lead, S-(E)-3-(1-(1-(benzo[d]oxazol-2-yl)-2-methylpropyl)-1H-1,2,3-triazol-4-yl)-N-hydroxyacrylamide (12, NK-HDAC-1), was discovered and showed about 1 order of magnitude more potency than SAHA in both enzymatic and cellular assays. For the in vitro safety tests, NK-HDAC-1 was far less toxic to nontransformed cells than tumor cells and showed no significant inhibition activity against CYP-3A4. The pharmaceutical properties (LogD, solubility, liver micrsomal stability (t1/2), plasma stability (t1/2), and apparent permeability) strongly suggested that NK-HDAC-1 might be superior to SAHA in bioavailability and in vivo half-life.