Synthesis and Biological Characterization of Amidopropenyl Hydroxamates as HDAC Inhibitors

• Published in: ChemMedChem Vol. 5; no. 8; pp. 1359 - 1372
• Main Authors: Thaler, Florian, Varasi, Mario, Colombo, Andrea, Boggio, Roberto, Munari, Davide, Regalia, Nickolas, Rozio, Marco G., Reali, Veronica, Resconi, Anna E., Mai, Antonello, Gagliardi, Stefania, Dondio, Giulio, Minucci, Saverio, Mercurio, Ciro
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 02.08.2010; WILEY‐VCH Verlag
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; antiproliferation; Cell Line, Tumor; Drug Screening Assays, Antitumor; Histone Deacetylase Inhibitors - chemical synthesis; Histone Deacetylase Inhibitors - chemistry; Histone Deacetylase Inhibitors - pharmacokinetics; histone deacetylases; Histone Deacetylases - chemistry; Histone Deacetylases - metabolism; Humans; hydroxamates; Hydroxamic Acids - chemical synthesis; Hydroxamic Acids - chemistry; Hydroxamic Acids - pharmacology; metabolism; Mice; Microsomes, Liver - metabolism; pharmacokinetics; Protein Isoforms - antagonists & inhibitors; Protein Isoforms - metabolism; Structure-Activity Relationship
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201000166

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 IC50 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. Potent and remarkably stable: Herein we summarize the synthesis and biological evaluation of a series of amidopropenyl hydroxamic acid derivatives as novel inhibitors of human histone deacetylases (HDAC). Selected compounds were studied for their in vivo pharmacokinetic behavior as well their metabolic stability in microsomal preparations and in hepatocytes.