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 preclinical profile

Wang, Haishan, Yu, Niefang, Chen, Dizhong, Lee, Ken Chi Lik, Lye, Pek Ling, Chang, Joyce Wei Wei, Deng, Weiping, Ng, Melvin Chi Yeh, Lu, Ting, Khoo, Mui Ling, Poulsen, Anders, Sangthongpitag, Kanda, Wu, Xiaofeng, Hu, Changyong, Goh, Kee Chuan, Wang, Xukun, Fang, Lijuan, Goh, Kay Lin, Khng, Hwee Hoon, Goh, Siok Kun, Yeo, Pauline, Liu, Xin, Bonday, Zahid, Wood, Jeanette M., Dymock, Brian W., Kantharaj, Kanthara and Sun, Eric T. (2011) 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 preclinical profile. Journal of Medicinal Chemistry, 54 13: 4694-4720. doi:10.1021/jm2003552


Author Wang, Haishan
Yu, Niefang
Chen, Dizhong
Lee, Ken Chi Lik
Lye, Pek Ling
Chang, Joyce Wei Wei
Deng, Weiping
Ng, Melvin Chi Yeh
Lu, Ting
Khoo, Mui Ling
Poulsen, Anders
Sangthongpitag, Kanda
Wu, Xiaofeng
Hu, Changyong
Goh, Kee Chuan
Wang, Xukun
Fang, Lijuan
Goh, Kay Lin
Khng, Hwee Hoon
Goh, Siok Kun
Yeo, Pauline
Liu, Xin
Bonday, Zahid
Wood, Jeanette M.
Dymock, Brian W.
Kantharaj, Kanthara
Sun, Eric T.
Title 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 preclinical profile
Formatted title
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 preclinical profile
Journal name Journal of Medicinal Chemistry   Check publisher's open access policy
ISSN 0022-2623
1520-4804
Publication date 2011-06-16
Sub-type Article (original research)
DOI 10.1021/jm2003552
Open Access Status
Volume 54
Issue 13
Start page 4694
End page 4720
Total pages 27
Place of publication Washington, DC, United States
Publisher American Chemical Society
Language eng
Formatted abstract
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 IC50), liver microsomal stability (t1/2), cytochrome P450 inhibitory (3A4 IC50), 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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
 
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Created: Fri, 27 Feb 2015, 14:32:10 EST by Dr Xin Liu on behalf of Medicine - Princess Alexandra Hospital