title: Oral administration of the pimelic diphenylamide HDAC inhibitor HDACi 4b is unsuitable for chronic inhibition of HDAC activity in the CNS in vivo.
abstract: Histone deacetylase (HDAC) inhibitors have received considerable attention as potential therapeutics for a variety of cancers and neurological disorders. Recent publications on a class of pimelic diphenylamide HDAC inhibitors have highlighted their promise in the treatment of the neurodegenerative diseases Friedreich's ataxia and Huntington's disease, based on efficacy in cell and mouse models. These studies' authors have proposed that the unique action of these compounds compared to hydroxamic acid-based HDAC inhibitors results from their unusual slow-on/slow-off kinetics of binding, preferentially to HDAC3, resulting in a distinctive pharmacological profile and reduced toxicity. Here, we evaluate the HDAC subtype selectivity, cellular activity, absorption, distribution, metabolism and excretion (ADME) properties, as well as the central pharmacodynamic profile of one such compound, HDACi 4b, previously described to show efficacy in vivo in the R6/2 mouse model of Huntington's disease. Based on our data reported here, we conclude that while the in vitro selectivity and binding mode are largely in agreement with previous reports, the physicochemical properties, metabolic and p-glycoprotein (Pgp) substrate liability of HDACi 4b render this compound suboptimal to investigate central Class I HDAC inhibition in vivo in mouse per oral administration. A drug administration regimen using HDACi 4b dissolved in drinking water was used in the previous proof of concept study, casting doubt on the validation of CNS HDAC3 inhibition as a target for the treatment of Huntington's disease. We highlight physicochemical stability and metabolic issues with 4b that are likely intrinsic liabilities of the benzamide chemotype in general.
authors.affiliation: CHDI Management/CHDI Foundation Inc., Los Angeles, California, United States of America.
authors.forename: Maria
authors.initials: M
authors.lastname: Beconi
authors.forename: Omar
authors.initials: O
authors.lastname: Aziz
authors.forename: Kim
authors.initials: K
authors.lastname: Matthews
authors.forename: Lara
authors.initials: L
authors.lastname: Moumné
authors.forename: Catherine
authors.initials: C
authors.lastname: O'Connell
authors.forename: Dawn
authors.initials: D
authors.lastname: Yates
authors.forename: Steven
authors.initials: S
authors.lastname: Clifton
authors.forename: Hannah
authors.initials: H
authors.lastname: Pett
authors.forename: Julie
authors.initials: J
authors.lastname: Vann
authors.forename: Lynsey
authors.initials: L
authors.lastname: Crowley
authors.forename: Alan F
authors.initials: AF
authors.lastname: Haughan
authors.forename: Donna L
authors.initials: DL
authors.lastname: Smith
authors.forename: Ben
authors.initials: B
authors.lastname: Woodman
authors.forename: Gillian P
authors.initials: GP
authors.lastname: Bates
authors.forename: Fred
authors.initials: F
authors.lastname: Brookfield
authors.forename: Roland W
authors.initials: RW
authors.lastname: Bürli
authors.forename: George
authors.initials: G
authors.lastname: McAllister
authors.forename: Celia
authors.initials: C
authors.lastname: Dominguez
authors.forename: Ignacio
authors.initials: I
authors.lastname: Munoz-Sanjuan
authors.forename: Vahri
authors.initials: V
authors.lastname: Beaumont
mesh_terms: D000284:Administration, Oral; D000818:Animals; D018938:Caco-2 Cells; D002490:Central Nervous System / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D005621:Friedreich Ataxia / Q000188:drug therapy* / Q000201:enzymology; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006816:Huntington Disease / Q000188:drug therapy* / Q000201:enzymology; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D010867:Pimelic Acids / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D053719:Tandem Mass Spectrometry
chemical_list: D056572:Histone Deacetylase Inhibitors; D010867:Pimelic Acids; C535010:pimelic diphenylamide 106; D006655:Histone Deacetylases