当前位置： SCI文献检索 > JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > 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.

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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Wang H,Yu N,Chen D,Lee KC,Lye PL,Chang JW,Deng W,Ng MC,Lu T,Khoo ML,Poulsen A,Sangthongpitag K,Wu X,Hu C,Goh KC,Wang X,Fang L,Goh KL,Khng HH,Goh SK,Yeo P,Liu X,Bonday Z,Wood JM,Dymock BW,Kantharaj E,Su

doi

10.1021/jm2003552

subject

Has Abstract

pub_date

2011-07-14 00:00:00

pages

4694-720

issue

13

eissn

0022-2623

issn

1520-4804

journal_volume

54

pub_type

杂志文章

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