Histone deacetylase (HDAC) inhibitors have received considerable attention as 
potential therapeutics for a variety of cancers and neurological disorders. 
Recent publications on a class of pimelic diphenylamide HDAC inhibitors have 
highlighted their promise in the treatment of the neurodegenerative diseases 
Friedreich's ataxia and Huntington's disease, based on efficacy in cell and 
mouse models. These studies' authors have proposed that the unique action of 
these compounds compared to hydroxamic acid-based HDAC inhibitors results from 
their unusual slow-on/slow-off kinetics of binding, preferentially to HDAC3, 
resulting in a distinctive pharmacological profile and reduced toxicity. Here, 
we evaluate the HDAC subtype selectivity, cellular activity, absorption, 
distribution, metabolism and excretion (ADME) properties, as well as the central 
pharmacodynamic profile of one such compound, HDACi 4b, previously described to 
show efficacy in vivo in the R6/2 mouse model of Huntington's disease. Based on 
our data reported here, we conclude that while the in vitro selectivity and 
binding mode are largely in agreement with previous reports, the physicochemical 
properties, metabolic and p-glycoprotein (Pgp) substrate liability of HDACi 4b 
render this compound suboptimal to investigate central Class I HDAC inhibition 
in vivo in mouse per oral administration. A drug administration regimen using 
HDACi 4b dissolved in drinking water was used in the previous proof of concept 
study, casting doubt on the validation of CNS HDAC3 inhibition as a target for 
the treatment of Huntington's disease. We highlight physicochemical stability 
and metabolic issues with 4b that are likely intrinsic liabilities of the 
benzamide chemotype in general.