title: Synthesis and evaluation of lysine derived sulfamides as histone deacetylase inhibitors.
abstract: We have recently reported on a novel class of histone deacetylase (HDAC) inhibitors bearing a sulfamide group as the zinc-binding unit. Herein, we report on the synthesis of sulfamide based inhibitors designed around a lysine scaffold and their structure-activity relationships against HDAC1 and HDAC6 isotypes as well as 293T cells. Our efforts led us to an improvement of the originally disclosed lysine-based sulfamide, 2a to compound 12h which has equal potency in enzyme and cell-based assays as well as enhanced metabolic stability and PK profile.
authors.affiliation: MethylGene Inc., Departments of Medicinal Chemistry, 7220 rue Frederick-Banting, Montreal, Quebec, Canada H4S 2A1.
authors.forename: Sukhdev
authors.initials: S
authors.lastname: Manku
authors.forename: Martin
authors.initials: M
authors.lastname: Allan
authors.forename: Natalie
authors.initials: N
authors.lastname: Nguyen
authors.forename: Alain
authors.initials: A
authors.lastname: Ajamian
authors.forename: Jacques
authors.initials: J
authors.lastname: Rodrigue
authors.forename: Eric
authors.initials: E
authors.lastname: Therrien
authors.forename: James
authors.initials: J
authors.lastname: Wang
authors.forename: Tim
authors.initials: T
authors.lastname: Guo
authors.forename: Jubrail
authors.initials: J
authors.lastname: Rahil
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Petschner
authors.forename: Alina
authors.initials: A
authors.lastname: Nicolescu
authors.forename: Sylvain
authors.initials: S
authors.lastname: Lefebvre
authors.forename: Zuomei
authors.initials: Z
authors.lastname: Li
authors.forename: Marielle
authors.initials: M
authors.lastname: Fournel
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Besterman
authors.forename: Robert
authors.initials: R
authors.lastname: Déziel
authors.forename: Amal
authors.initials: A
authors.lastname: Wahhab
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D002352:Carrier Proteins / Q000737:chemistry; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000737:chemistry; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D001562:Benzimidazoles; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D020033:Protein Isoforms; D013449:Sulfonamides; C017800:zinc-binding protein; D006655:Histone Deacetylases; D008239:Lysine