Oral Administration of the Pimelic Diphenylamide HDAC Inhibitor HDACi 4b Is Unsuitable for Chronic Inhibition of HDAC Activity in the CNS In Vivo

Abstract

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.

HDAC inhibition imparts beneficial transgenerational effects in Huntington's disease mice via altered DNA and histone methylation

“…HDACi 4b was dissolved with 75% (vol/vol) polyethylene glycol 200; control mice received double-distilled H 2 O containing an equal volume of drug vehicle. Our previous studies have found that the s.c. injection paradigm for HDACi 4b is optimal for improving disease phenotypes in N171-82Q transgenic mice, given the poor solubility of HDACi 4b for drinking water paradigms (44,45).…”

Therapeutic Potential of Isoform Selective Hdac Inhibitors for the Treatment of Schizophrenia

“…The effects of RGFP136 recapitulated the behavioral effects that were observed in HDAC3 f loxed C57BL/6 mice. However, reports examining the stability and pharmacokinetic properties of this class of compounds have raised concerns about the applicability of these compounds in model systems of disease [57]. More recently, Repligen Corp. has reported a series of heterocinnamyl linked ortho-aminoanilides, RGFP966, that display high selectivity for HDAC3 (FiguRe 8).…”

Transcriptional dysregulation in Huntington’s disease: The role of histone deacetylases

“…Moreover, a recent publication has questioned the use of oral administration of the HDACI 4b in vivo in mouse models [134]. These authors demonstrated that based on physicochemical properties, metabolic and p-glycoprotein substrate liability, the compound 4b, is suboptimal to investigate inhibition in vivo in mouse models using oral administration [134].…”

“…These authors demonstrated that based on physicochemical properties, metabolic and p-glycoprotein substrate liability, the compound 4b, is suboptimal to investigate inhibition in vivo in mouse models using oral administration [134]. Undoubtedly, more studies have to be performed using other methods of delivery as well as assessing effects in more slowly progressing HD models to better evaluate the effects of this HDAC inhibitor.…”