5-Aroylindoles Act as Selective Histone Deacetylase 6 Inhibitors Ameliorating Alzheimer's Disease Phenotypes

  • J Med Chem. 2018 Aug 23;61(16):7087-7102. doi: 10.1021/acs.jmedchem.8b00151.
Hsueh-Yun Lee  1 ,  Sheng-Jun Fan  2 ,  Fang-I Huang  2 ,  Hsin-Yi Chao  1 ,  Kai-Cheng Hsu  3 ,  Tony Eight Lin  3 ,  Teng-Kuang Yeh  4 ,  Mei-Jung Lai  5 ,  Yu-Hsuan Li  1 ,  Hsiang-Ling Huang  1 ,  Chia-Ron Yang  2 ,  Jing-Ping Liou  1
Affiliations
  • 1. School of Pharmacy, College of Pharmacy , Taipei Medical University , 250 Wuxing Street , Taipei 11031 , Taiwan.
  • 2. School of Pharmacy, College of Medicine , National Taiwan University , Taipei 10607 , Taiwan.
  • 3. Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology , Taipei Medical University , Taipei 11031 , Taiwan.
  • 4. Institute of Biotechnology and Pharmaceutical Research , National Health Research Institutes , Zhunan Town , Miaoli County 35053 , Taiwan.
  • 5. Research Center of Cancer Translational Medicine , Taipei Medical University , Taipei 11031 , Taiwan.
PMID: 30028616 DOI: 10.1021/acs.jmedchem.8b00151
Abstract

This paper reports the development of a series of 5-aroylindolyl-substituted hydroxamic acids. N-Hydroxy-4-((5-(4-methoxybenzoyl)-1 H-indol-1-yl)methyl)benzamide (6) has potent inhibitory selectivity against histone deacetylase 6 (HDAC6) with an IC50 value of 3.92 nM. It decreases not only the level of phosphorylation of tau proteins but also the aggregation of tau proteins. Compound 6 also shows neuroprotective activity by triggering ubiquitination. In animal models, compound 6 is able to ameliorate the impaired learning and memory, and it crosses the blood-brain barrier after oral administration. Compound 6 can be developed as a potential treatment for Alzheimer's disease in the future.

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