Abstract
Optimisation of ADS100380, a sub-micromolar HDAC inhibitor identified using a virtual screening approach, led to a series of substituted 5-(1H-pyrazol-3-yl)-thiophene-2-hydroxamic acids (6a-i), that possessed significant HDAC inhibitory activity. Subsequent functionalisation of the pendent phenyl group of compounds 6f and 6g provided analogues 6j-w with further enhanced enzyme and anti-proliferative activity. Compound 6j demonstrated efficacy in a mouse xenograft experiment.
MeSH terms
-
Animals
-
Antineoplastic Agents / chemical synthesis
-
Antineoplastic Agents / pharmacology
-
Biological Availability
-
Cell Line, Tumor
-
Cell Proliferation / drug effects
-
Computer Simulation
-
Drug Evaluation, Preclinical
-
Enzyme Inhibitors / chemical synthesis*
-
Enzyme Inhibitors / pharmacokinetics
-
Enzyme Inhibitors / pharmacology*
-
Histone Deacetylase Inhibitors*
-
Humans
-
Hydroxamic Acids / chemical synthesis*
-
Hydroxamic Acids / pharmacology*
-
Indicators and Reagents
-
Mice
-
Neoplasm Transplantation
-
Neoplasms, Experimental / drug therapy
-
Pyrazoles / chemical synthesis*
-
Pyrazoles / pharmacology*
-
Rats
-
Structure-Activity Relationship
-
Transplantation, Heterologous
Substances
-
Antineoplastic Agents
-
Enzyme Inhibitors
-
Histone Deacetylase Inhibitors
-
Hydroxamic Acids
-
Indicators and Reagents
-
Pyrazoles