929018-74-6Relevant articles and documents
Discovery of (2 E)-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, Ethirajulu,Sun, Eric T.
, p. 4694 - 4720 (2011/09/15)
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 50), 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.
