title: Improved Histone Deacetylase Inhibitors as Therapeutics for the Neurodegenerative Disease Friedreich's Ataxia: A New Synthetic Route.
abstract: 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.
authors.affiliation: Department of Molecular Biology, The Scripps Research Institute, 10550 N. Torreys Pines Road, La Jolla, CA 92037, USA. chpxu@scripps.edu.
authors.forename: Chunping
authors.initials: C
authors.lastname: Xu
authors.affiliation: Department of Molecular Biology, The Scripps Research Institute, 10550 N. Torreys Pines Road, La Jolla, CA 92037, USA. soragni@scripps.edu.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Soragni
authors.affiliation: Repligen Corporation, 41 Seyon Street, Waltham, MA 02453, USA. vjacques@repligen.com.
authors.forename: Vincent
authors.initials: V
authors.lastname: Jacques
authors.affiliation: Repligen Corporation, 41 Seyon Street, Waltham, MA 02453, USA. jrusche@repligen.com.
authors.forename: James R
authors.initials: JR
authors.lastname: Rusche
authors.affiliation: Department of Molecular Biology, The Scripps Research Institute, 10550 N. Torreys Pines Road, La Jolla, CA 92037, USA. joelg@scripps.edu.
authors.forename: Joel M
authors.initials: JM
authors.lastname: Gottesfeld
keywords: Friedreich’s ataxia; HDAC inhibitor; click chemistry