Diphenylmethylene hydroxamic acids as selective class IIa histone deacetylase inhibitors

We have identified a series of diphenylmethylene hydroxamic acids as novel and selective HDAC class IIa inhibitors. The original hit, N-hydroxy-2,2-diphenylacetamide (6), has sub-micromolar class IIa HDAC inhibitory activity, while the rigidified oxygen analogue, N-hydroxy-9H-xanthene-9-carboxamide (13), is slightly more selective for HDAC7 with an IC50 of 0.05 μM. Substitution of 6 allows for the modulation of selectivity and potency amongst the class IIa HDAC isotypes.

We have identified a series of diphenylmethylene hydroxamic acids as novel and selective HDAC class IIa inhibitors. N-Hydroxy-2,2-diphenylacetamide (6), has class IIa HDAC inhibitory activity in the sub-micromolar range, while the rigidified N-hydroxy-9H-xanthene-9-carboxamide (13), is slightly more selective for HDAC7. Substitution of 6 allows for the modulation of selectivity and potency amongst the class IIa HDAC isotypes.Figure optionsDownload as PowerPoint slide