2. Academic Validation
  3. 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

  • 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

Affiliation

  • 1 Chemistry Discovery, S*BIO Pte Ltd., The Capricorn, Singapore Science Park II, Singapore, Singapore. haishan_wang@sbio.com
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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