Discovery of (2E)-3-{2-Butyl-1-[2-(diethylamino)ethyl]-1H-benzimidazol-5-yl}-N-hydroxyacrylamide (SB939), an Orally Active Histone Deacetylase Inhibitor with a Superior Preclinica

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• 作者：Haishan Wang ; Niefang Yu ; Dizhong Chen ; Ken Chi Lik Lee ; Pek Ling Lye ; Joyce Wei Wei Chang ; Weiping Deng ; Melvin Chi Yeh Ng ; Ting Lu ; Mui Ling Khoo ; Anders Poulsen ; Kanda Sangthongpitag ; Xiaofeng Wu ; Changyong Hu ; Kee Chuan Goh ; Xukun Wang ; Lijuan Fang ; Kay Lin Goh ; Hwee Hoon Khng ; Siok Kun Goh ; Pauline Yeo ; Xin Liu ; Zahid Bonday ; Jeanette M. Wood ; Brian W. Dymock ; Kantharaj Ethirajulu ; Eric T. Sun
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：July 14, 2011
• 年：2011
• 卷：54
• 期：13
• 页码：4694-4720
• 全文大小：1612K
• 年卷期：v.54,no.13(July 14, 2011)
• ISSN：1520-4804

文摘

A series of 3-(1,2-disubstituted-1H-benzimidazol-5-yl)-N-hydroxyacrylamides (1) were designed and synthesized as HDAC inhibitors. Extensive SARs have been established for in vitro potency (HDAC1 enzyme and COLO 205 cellular IC<sub>50sub>), liver microsomal stability (t<sub>1/2sub>), cytochrome P450 inhibitory (3A4 IC<sub>50sub>), and clogP, among others. These parameters were fine-tuned by carefully adjusting the substituents at positions 1 and 2 of the benzimidazole ring. After comprehensive in vitro and in vivo profiling of the selected compounds, SB939 (3) was identified as a preclinical development candidate. 3 is a potent pan-HDAC inhibitor with excellent druglike properties, is highly efficacious in in vivo tumor models (HCT-116, PC-3, A2780, MV4-11, Ramos), and has high and dose-proportional oral exposures and very good ADME, safety, and pharmaceutical properties. When orally dosed to tumor-bearing mice, 3 is enriched in tumor tissue which may contribute to its potent antitumor activity and prolonged duration of action. 3 is currently being tested in phase I and phase II clinical trials.