Abstract
A novel series of HDAC inhibitors demonstrating class I subtype selectivity and good oral bioavailability is described. The compounds are potent enzyme inhibitors (IC₅₀ values less than 100 nM), and improved activity in cell proliferation assays was achieved by modulation of polar surface area (PSA) through the introduction of novel linking groups. Employing oral pharmacokinetic studies in mice, comparing drug levels in spleen to plasma, we selected compounds that were tested for efficacy in human tumor xenograft studies based on their potential to distribute into tumor. One compound, 21r (CHR-3996), showed good oral activity in these models, including dose-related activity in a LoVo xenograft. In addition 21r showed good activity in combination with other anticancer agents in in vitro studies. On the basis of these results, 21r was nominated for clinical development.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Antineoplastic Agents / chemical synthesis*
-
Antineoplastic Agents / pharmacokinetics
-
Antineoplastic Agents / pharmacology
-
Azabicyclo Compounds / chemical synthesis*
-
Azabicyclo Compounds / pharmacokinetics
-
Azabicyclo Compounds / pharmacology
-
Cell Line, Tumor
-
Dogs
-
Drug Screening Assays, Antitumor
-
Drug Synergism
-
Female
-
Histone Deacetylase Inhibitors / chemical synthesis*
-
Histone Deacetylase Inhibitors / pharmacokinetics
-
Histone Deacetylase Inhibitors / pharmacology
-
Humans
-
In Vitro Techniques
-
Mice
-
Mice, Nude
-
Microsomes, Liver / metabolism
-
Models, Molecular
-
Neoplasm Transplantation
-
Pyrimidines / chemical synthesis*
-
Pyrimidines / pharmacokinetics
-
Pyrimidines / pharmacology
-
Rats
-
Stereoisomerism
-
Structure-Activity Relationship
-
Tissue Distribution
-
Transplantation, Heterologous
Substances
-
2-(6-(((6-fluoroquinolin-2-yl)methyl)amino)bicyclo(3.1.0)hex-3-yl)-N-hydroxypyrimidine-5-carboxamide
-
Antineoplastic Agents
-
Azabicyclo Compounds
-
Histone Deacetylase Inhibitors
-
Pyrimidines