Next Article in Journal
Targeted CRM197-PEG-PEI/siRNA Complexes for Therapeutic RNAi in Glioblastoma
Previous Article in Journal
Proteolytically Derived Endogenous Angioinhibitors Originating from the Extracellular Matrix
Previous Article in Special Issue
Histone Deacetylase Inhibitors and Mithramycin A Impact a Similar Neuroprotective Pathway at a Crossroad between Cancer and Neurodegeneration
Article Menu

Export Article

Open AccessArticle
Pharmaceuticals 2011, 4(12), 1578-1590;

Improved Histone Deacetylase Inhibitors as Therapeutics for the Neurodegenerative Disease Friedreich’s Ataxia: A New Synthetic Route

Department of Molecular Biology, The Scripps Research Institute, 10550 N. Torreys Pines Road, La Jolla, CA 92037, USA
Repligen Corporation, 41 Seyon Street, Waltham, MA 02453, USA
Author to whom correspondence should be addressed.
Received: 18 October 2011 / Revised: 30 November 2011 / Accepted: 30 November 2011 / Published: 14 December 2011
(This article belongs to the Special Issue HDAC Inhibitors)
Full-Text   |   PDF [368 KB, uploaded 14 December 2011]


Friedreich’s ataxia (FRDA) is caused by transcriptional repression of the nuclear FXN gene encoding the essential mitochondrial protein frataxin. Based on the hypothesis that the acetylation state of the histone proteins is responsible for gene silencing in FRDA, previous work in our lab identified a first generation of HDAC inhibitors (pimelic o-aminobenzamides), which increase FXN mRNA in lymphocytes from FRDA patients. Importantly, these compounds also function in a FRDA mouse model to increase FXN mRNA levels in the brain and heart. While the first generation of HDAC inhibitors hold promise as potential therapeutics for FRDA, they have two potential problems: less than optimal brain penetration and metabolic instability in acidic conditions. Extensive optimization focusing on modifying the left benzene ring, linker and the right benzene ring lead to a novel class of HDAC inhibitors that have optimized pharmacological properties (increased brain penetration and acid stability) compared to the previous HDAC inhibitors. This article will describe the chemical synthesis and pharmacological properties of these new HDAC inhibitors. View Full-Text
Keywords: HDAC inhibitor; Friedreich’s ataxia; click chemistry HDAC inhibitor; Friedreich’s ataxia; click chemistry
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

Share & Cite This Article

MDPI and ACS Style

Xu, C.; Soragni, E.; Jacques, V.; Rusche, J.R.; Gottesfeld, J.M. Improved Histone Deacetylase Inhibitors as Therapeutics for the Neurodegenerative Disease Friedreich’s Ataxia: A New Synthetic Route. Pharmaceuticals 2011, 4, 1578-1590.

Show more citation formats Show less citations formats

Related Articles

Article Metrics

Article Access Statistics



[Return to top]
Pharmaceuticals EISSN 1424-8247 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top