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

  • J Med Chem. 2011 Jul 14;54(13):4694-720. doi: 10.1021/jm2003552.
Haishan Wang  1 ,  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
Affiliations
  • 1. Chemistry Discovery, S*BIO Pte Ltd., The Capricorn, Singapore Science Park II, Singapore, Singapore. [email protected]
PMID: 21634430 DOI: 10.1021/jm2003552
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.

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