title: Synthesis and biological characterization of amidopropenyl hydroxamates as HDAC inhibitors.
abstract: A series of amidopropenyl hydroxamic acid derivatives were prepared as novel inhibitors of human histone deacetylases (HDACs). Several compounds showed potency at <100 nM in the HDAC inhibition assays, sub-micromolar IC(50) values in tests against three tumor cell lines, and remarkable stability in human and mouse microsomes was observed. Three representative compounds were selected for further characterization and submitted to a selectivity profile against a series of class I and class II HDACs as well as to preliminary in vivo pharmacokinetic (PK) experiments. Despite their high microsomal stability, the compounds showed medium-to-high clearance rates in in vivo PK studies as well as in rat and human hepatocytes, indicating that a major metabolic pathway is catalyzed by non-microsomal enzymes.
authors.affiliation: Genextra Group, Congenia s.r.l., Milan, Italy. florian.thaler@ifom-ieo-campus.it
authors.forename: Florian
authors.initials: F
authors.lastname: Thaler
authors.forename: Mario
authors.initials: M
authors.lastname: Varasi
authors.forename: Andrea
authors.initials: A
authors.lastname: Colombo
authors.forename: Roberto
authors.initials: R
authors.lastname: Boggio
authors.forename: Davide
authors.initials: D
authors.lastname: Munari
authors.forename: Nickolas
authors.initials: N
authors.lastname: Regalia
authors.forename: Marco G
authors.initials: MG
authors.lastname: Rozio
authors.forename: Veronica
authors.initials: V
authors.lastname: Reali
authors.forename: Anna E
authors.initials: AE
authors.lastname: Resconi
authors.forename: Antonello
authors.initials: A
authors.lastname: Mai
authors.forename: Stefania
authors.initials: S
authors.lastname: Gagliardi
authors.forename: Giulio
authors.initials: G
authors.lastname: Dondio
authors.forename: Saverio
authors.initials: S
authors.lastname: Minucci
authors.forename: Ciro
authors.initials: C
authors.lastname: Mercurio
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D006655:Histone Deacetylases / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D020033:Protein Isoforms; D006655:Histone Deacetylases