Abstract
Recent studies have revealed that several histone deacetylase (HDAC) inhibitors, which are used to study/treat brain diseases, show low blood-brain barrier (BBB) penetration. In addition to low HDAC potency and selectivity observed, poor brain penetrance may account for the high doses needed to achieve therapeutic efficacy. Here we report the development and evaluation of highly potent and blood-brain barrier permeable HDAC inhibitors for CNS applications based on an image-guided approach involving the parallel synthesis and radiolabeling of a series of compounds based on the benzamide HDAC inhibitor, MS-275 as a template. BBB penetration was optimized by rapid carbon-11 labeling and PET imaging in the baboon model and using the imaging derived data on BBB penetration from each compound to feed back into the design process. A total of 17 compounds were evaluated, revealing molecules with both high binding affinity and BBB permeability. A key element conferring BBB penetration in this benzamide series was a basic benzylic amine. These derivatives exhibited 1-100 nM inhibitory activity against recombinant human HDAC1 and HDAC2. Three of the carbon-11 labeled aminomethyl benzamide derivatives showed high BBB penetration (∼0.015%ID/cc) and regional binding heterogeneity in the brain (high in thalamus and cerebellum). Taken together this approach has afforded a strategy and a predictive model for developing highly potent and BBB permeable HDAC inhibitors for CNS applications and for the discovery of novel candidate molecules for small molecule probes and drugs.
Highlights
Epigenetic regulation of gene expression via enzymatic modification of DNA and histone proteins is implicated in development,[1] inflammation,[2] heart disease,[3] cancer,[4] and neuropsychiatric disorders[5,6] including depression, Alzheimer’s disease, and substance use disorders
We found that the benzamide HDAC inhibitors (HDACi), MS-275 (6), has low brain uptake when administered intravenously to nonhuman primates,[17] suggesting its limitation as a therapeutic agent for central nervous system (CNS) disorders
The development of a blood-brain barrier (BBB) permeable histone deacetylase (HDAC) inhibitor is based on an iterative plan with four components: in silico structural design and prediction, parallel synthesis and in ACS Chemical Neuroscience Table 1
Summary
Epigenetic regulation of gene expression via enzymatic modification of DNA and histone proteins is implicated in development,[1] inflammation,[2] heart disease,[3] cancer,[4] and neuropsychiatric disorders[5,6] including depression, Alzheimer’s disease, and substance use disorders. HDAC removes an acetyl group of histone proteins (by hydrolysis of acetamido group of ε-carbon of lysine residues), inducing a tight charge− charge interaction between DNA and histone proteins, thereby rendering the DNA inaccessible to transcription factor binding and repressing gene expression. Though mostly investigated for the treatment of cancer, an increasing numbers of studies are evaluating HDACi for central nervous system (CNS) diseases, such as schizophrenia, neurodegenerative disorders, seizures, depression, and addiction.[11−15] One potential advantage of HDAC drugs is the potential for reversing abnormal cell transcription, rather than treating downstream translational endophenotypes. The potential therapeutic benefits that HDACi might confer in CNS disorders stimulated us to investigate the brain uptake of a number of well-known HDAC inhibitors as potential templates for the development of highly potent blood-brain barrier (BBB) permeable HDAC inhibitors for CNS applications. A systematic approach to better predict BBB penetration of small molecule probes and drugs for CNS therapeutics is needed, including that for HDACi.[19]
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