title: Design, synthesis, and biological evaluation of potent and selective class IIa histone deacetylase (HDAC) inhibitors as a potential therapy for Huntington's disease.
abstract: Inhibition of class IIa histone deacetylase (HDAC) enzymes have been suggested as a therapeutic strategy for a number of diseases, including Huntington's disease. Catalytic-site small molecule inhibitors of the class IIa HDAC4, -5, -7, and -9 were developed. These trisubstituted diarylcyclopropanehydroxamic acids were designed to exploit a lower pocket that is characteristic for the class IIa HDACs, not present in other HDAC classes. Selected inhibitors were cocrystallized with the catalytic domain of human HDAC4. We describe the first HDAC4 catalytic domain crystal structure in a "closed-loop" form, which in our view represents the biologically relevant conformation. We have demonstrated that these molecules can differentiate class IIa HDACs from class I and class IIb subtypes. They exhibited pharmacokinetic properties that should enable the assessment of their therapeutic benefit in both peripheral and CNS disorders. These selective inhibitors provide a means for evaluating potential efficacy in preclinical models in vivo.
authors.affiliation: BioFocus , Chesterford Research Park, Saffron Walden, Essex, CB10 1XL, United Kingdom.
authors.forename: Roland W
authors.initials: RW
authors.lastname: Bürli
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Luckhurst
authors.forename: Omar
authors.initials: O
authors.lastname: Aziz
authors.forename: Kim L
authors.initials: KL
authors.lastname: Matthews
authors.forename: Dawn
authors.initials: D
authors.lastname: Yates
authors.forename: Kathy A
authors.initials: KA
authors.lastname: Lyons
authors.forename: Maria
authors.initials: M
authors.lastname: Beconi
authors.forename: George
authors.initials: G
authors.lastname: McAllister
authors.forename: Perla
authors.initials: P
authors.lastname: Breccia
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Stott
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Penrose
authors.forename: Michael
authors.initials: M
authors.lastname: Wall
authors.forename: Marieke
authors.initials: M
authors.lastname: Lamers
authors.forename: Philip
authors.initials: P
authors.lastname: Leonard
authors.forename: Ilka
authors.initials: I
authors.lastname: Müller
authors.forename: Christine M
authors.initials: CM
authors.lastname: Richardson
authors.forename: Rebecca
authors.initials: R
authors.lastname: Jarvis
authors.forename: Liz
authors.initials: L
authors.lastname: Stones
authors.forename: Samantha
authors.initials: S
authors.lastname: Hughes
authors.forename: Grant
authors.initials: G
authors.lastname: Wishart
authors.forename: Alan F
authors.initials: AF
authors.lastname: Haughan
authors.forename: Catherine
authors.initials: C
authors.lastname: O'Connell
authors.forename: Tania
authors.initials: T
authors.lastname: Mead
authors.forename: Hannah
authors.initials: H
authors.lastname: McNeil
authors.forename: Julie
authors.initials: J
authors.lastname: Vann
authors.forename: John
authors.initials: J
authors.lastname: Mangette
authors.forename: Michel
authors.initials: M
authors.lastname: Maillard
authors.forename: Vahri
authors.initials: V
authors.lastname: Beaumont
authors.forename: Ignacio
authors.initials: I
authors.lastname: Munoz-Sanjuan
authors.forename: Celia
authors.initials: C
authors.lastname: Dominguez
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000145:classification / Q000378:metabolism*; D006801:Humans; D006816:Huntington Disease / Q000188:drug therapy*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D056572:Histone Deacetylase Inhibitors; D007527:Isoenzymes; D006655:Histone Deacetylases