Image-guided synthesis reveals potent blood-brain barrier permeable histone deacetylase inhibitors.
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.
Biosciences Department, Brookhaven National Laboratory , Upton, New York 11973, United States.
Young Jun
YJ
Seo
Yeona
Y
Kang
Lisa
L
Muench
Alicia
A
Reid
Shannon
S
Caesar
Logan
L
Jean
Florence
F
Wagner
Edward
E
Holson
Stephen J
SJ
Haggarty
Philipp
P
Weiss
Payton
P
King
Pauline
P
Carter
Nora D
ND
Volkow
Joanna S
JS
Fowler
Jacob M
JM
Hooker
Sung Won
SW
Kim
D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D002199:Capillary Permeability; D002250:Carbon Radioisotopes; D004341:Drug Evaluation / Q000379:methods; D005260:Female; D056284:Histone Deacetylase 1 / Q000737:chemistry; D056464:Histone Deacetylase 2 / Q000737:chemistry; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D048530:Papio anubis; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D011994:Recombinant Proteins / Q000737:chemistry
D001549:Benzamides; D002250:Carbon Radioisotopes; D056572:Histone Deacetylase Inhibitors; D019275:Radiopharmaceuticals; D011994:Recombinant Proteins; C110550:HDAC1 protein, human; C533423:HDAC2 protein, human; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2