Synthesis and biological characterization of amidopropenyl hydroxamates as HDAC inhibitors.
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.
Thaler
Florian
F
Genextra Group, Congenia s.r.l., Milan, Italy. florian.thaler@ifom-ieo-campus.it
Varasi
Mario
M
Colombo
Andrea
A
Boggio
Roberto
R
Munari
Davide
D
Regalia
Nickolas
N
Rozio
Marco G
MG
Reali
Veronica
V
Resconi
Anna E
AE
Mai
Antonello
A
Gagliardi
Stefania
S
Dondio
Giulio
G
Minucci
Saverio
S
Mercurio
Ciro
C
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
D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D020033:Protein Isoforms; D006655:Histone Deacetylases