Discovery of (2 E)-3-{2-butyl-1-[2-(diethylamino) ethyl]-1 H-benzimidazol-5-yl}-N-hydroxyacrylamide (SB939), an orally active histone deacetylase inhibitor with a …

…, ML Khoo, A Poulsen, K Sangthongpitag…

Index: 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. Journal of Medicinal Chemistry, 2011 , vol. 54, # 13 p. 4694 - 4720

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Citation Number: 35

Abstract

A series of 3-(1, 2-disubstituted-1 H-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 (t 1/2), 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 ...