Exploring the pharmacokinetic properties of phosphorus-containing selective HDAC 1 and 2 inhibitors (SHI-1:2)

We report the preparation and structure-activity relationships of phosphorus-containing histone deacetylase inhibitors. A strong trend between decreasing phosphorus functional group size and superior mouse pharmacokinetic properties was identified. In addition, optimized candidates showed tumor grow...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2009-04, Vol.19 (7), p.2053-2058
Main Authors: HEIDEBRECHT, Richard W, CHENARD, Melissa, KRAL, Astrid M, MIDDLETON, Richard E, MUSHTI, Chandrasekhar, OZEROVA, Nicole, SZEWCZAK, Alexander A, HONGMEI WANG, WILSON, Kevin, WITTER, David J, SECRIST, J. Paul, MILLER, Thomas A, CLOSE, Joshua, DAHLBERG, William K, FLEMING, Judith, GRIMM, Jonathan B, HAMILL, Julie E, HARSCH, Andreas, HAINES, Brian B, HUGHES, Bethany
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Antineoplastic agents
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacokinetics
Biological and medical sciences
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacokinetics
General aspects
Histone Deacetylase 1
Histone Deacetylase 2
Histone Deacetylase Inhibitors
Histone Deacetylases - metabolism
Medical sciences
Mice
Mice, Nude
Organophosphonates - chemical synthesis
Organophosphonates - chemistry
Organophosphonates - pharmacokinetics
Pharmacology. Drug treatments
Repressor Proteins - antagonists & inhibitors
Repressor Proteins - metabolism
Transplantation, Heterologous
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Summary:We report the preparation and structure-activity relationships of phosphorus-containing histone deacetylase inhibitors. A strong trend between decreasing phosphorus functional group size and superior mouse pharmacokinetic properties was identified. In addition, optimized candidates showed tumor growth inhibition in xenograft studies.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2009.02.009