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.

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 IC(50)), liver microsomal stability (t(1/2)), cytochrome P450 inhibitory (3A4 IC(50)), 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.
Authors	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, Ethirajulu Kantharaj, Eric T Sun
Journal	Journal of medicinal chemistry (J Med Chem) Vol. 54 Issue 13 Pg. 4694-720 (Jul 14 2011) ISSN: 1520-4804 [Electronic] United States
PMID	21634430 (Publication Type: Journal Article)
Chemical References	Antineoplastic Agents Benzimidazoles Histone Deacetylase Inhibitors Isoenzymes SB939 compound Histone Deacetylase 1
Topics	Administration, Oral Animals Antineoplastic Agents (chemical synthesis, pharmacokinetics, pharmacology) Benzimidazoles (chemical synthesis, pharmacokinetics, pharmacology) Biological Availability Cell Line, Tumor Dogs Drug Screening Assays, Antitumor Female Histone Deacetylase 1 (antagonists & inhibitors) Histone Deacetylase Inhibitors (chemical synthesis, pharmacokinetics, pharmacology) Humans Isoenzymes (antagonists & inhibitors, metabolism) Mice Mice, Inbred BALB C Mice, Nude Microsomes, Liver (metabolism) Neoplasm Transplantation Quantitative Structure-Activity Relationship Rats Rats, Wistar Stereoisomerism

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