Discovery and Extensive in Vitro Evaluations of NK-HDAC-1: A Chiral Histone Deacetylase Inhibitor as a Promising Lead
Discovery and Extensive in Vitro Evaluations of NK-HDAC-1: A Chiral Histone Deacetylase Inhibitor as a Promising Lead
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NK-HDAC-1 的发现和广泛的体外评估：作为一种有前景的先导物的手性组蛋白脱乙酰酶抑制剂
DOI：
10.1021/jm201496g
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发表时间：
2012-04-12
影响因子：
7.3
通讯作者：
Wang, Peng George
中科院分区：
文献类型：
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作者：
Hou, Jingli;Li, Zhonghua;Wang, Peng George
在此，对先导化合物NSC746457进行了进一步的合成孔径雷达(SAR)研究。P.G.J.医学院。化学。2008，SI，7417-7427)，包括用2-取代苯并杂芳环取代反式-苯乙烯基部分和在中心亚甲基碳上引入取代基。一种很有前途的手性先导化合物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)被发现，在酶和细胞分析中显示出比SAHA高一个数量级的效力。在体外安全性测试中，NK-HDAC-1对未转化细胞的毒性远低于肿瘤细胞，并且对CYP-3A4没有明显的抑制活性。药物性质(LogD、溶解度、肝微球稳定性(t1/2)、血浆稳定性(t1/2)和表观通透性)强烈提示NK-HDAC-1在生物利用度和体内半衰期方面优于SAHA。
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, SI, 7417-7427) 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.