HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Design, synthesis and biological evaluation of dual-function inhibitors targeting NMDAR and HDAC for Alzheimer's disease.

Abstract
Histone deacetylases (HDACs) have been indicated important roles in neurodegenerative disorders including Alzheimer's disease (AD). Herein, a series of novel compounds that contain a memantine moiety were designed to target HDACs and N-methyl-d-aspartate receptor (NMDAR) which are related to the treatment of AD. Biological characterization established that compound 9d exhibited a balanced inhibitory activity on NMDAR and HDACs. This compound is relatively selective to HDAC6 with IC50 of 0.18 μM and also maintains comparable activity on NMDAR (Ki = 0.59 μM) as memantine. Functionally, treatment with 9d increased the level of AcTubulin in MV4-11 cells and rescued PC-12 cells from H2O2-induced cytotoxicity with EC50 of 0.94 μM. Studies in mice also demonstrated that compound 9d efficiently penetrates the blood brain barrier to reach the brain tissue. Collectively, the results strongly encourage further development of 9d as a potential therapeutic agent for AD.
AuthorsFeng He, Yingying Ran, Xiaoyang Li, Defeng Wang, Qiuqiong Zhang, Jiahui Lv, Chenggong Yu, Ying Qu, Xiangna Zhang, Ana Xu, Chao Wei, C James Chou, Jingde Wu
JournalBioorganic chemistry (Bioorg Chem) Vol. 103 Pg. 104109 (10 2020) ISSN: 1090-2120 [Electronic] United States
PMID32768741 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2020 Elsevier Inc. All rights reserved.
Chemical References
  • Histone Deacetylase Inhibitors
  • Isoenzymes
  • Neuroprotective Agents
  • Receptors, N-Methyl-D-Aspartate
  • Hydrogen Peroxide
  • Histone Deacetylases
Topics
  • Alzheimer Disease (drug therapy, metabolism)
  • Animals
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Drug Design
  • Histone Deacetylase Inhibitors (chemical synthesis, chemistry, pharmacology)
  • Histone Deacetylases (metabolism)
  • Humans
  • Hydrogen Peroxide (antagonists & inhibitors, pharmacology)
  • Isoenzymes (antagonists & inhibitors, metabolism)
  • Molecular Structure
  • Neuroprotective Agents (chemical synthesis, chemistry, pharmacology)
  • PC12 Cells
  • Rats
  • Receptors, N-Methyl-D-Aspartate (antagonists & inhibitors, metabolism)
  • Structure-Activity Relationship

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: