Abstract
Polo-like kinase-2 (Plk-2) is a potential therapeutic target for Parkinson's disease and this Letter describes the SAR of a series of dihydropteridinone based Plk-2 inhibitors. By optimizing both the N-8 substituent and the biaryl region of the inhibitors we obtained single digit nanomolar compounds such as 37 with excellent selectivity for Plk-2 over Plk-1. When dosed orally in rats, compound 37 demonstrated a 41-45% reduction of pS129-α-synuclein levels in the cerebral cortex.
Copyright © 2013 Elsevier Ltd. All rights reserved.
MeSH terms
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Administration, Oral
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Animals
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Brain / metabolism
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Cell Cycle Proteins / antagonists & inhibitors
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Cell Cycle Proteins / metabolism
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Drug Design*
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HEK293 Cells
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Half-Life
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Humans
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Mice
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Microsomes, Liver / metabolism
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Polo-Like Kinase 1
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Protein Kinase Inhibitors / chemical synthesis*
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / metabolism
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Pteridines / chemical synthesis
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Pteridines / chemistry
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Pteridines / pharmacokinetics
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Rats
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Structure-Activity Relationship
Substances
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Cell Cycle Proteins
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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Pteridines
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PLK2 protein, human
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Protein Serine-Threonine Kinases