Abstract
The synthesis and structure-activity relationship studies of a series of compounds from imidazopyridazinone scaffold as PDE7 inhibitors are disclosed. Potent analogs such as compounds 7 (31nM), 8 (27nM), and 9 (12nM) were identified. The PDE selectivity and pharmacokinetic profile of compounds 7, 8 and 9 are also disclosed. The adequate CNS penetration of compound 7 in mice allowed it to be tested in the MPTP induced PD model and haloperidol induced catalepsy model to probe the differential pharmacology of PDE7 in the striatal pathway.
Copyright © 2012 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Cyclic Nucleotide Phosphodiesterases, Type 7 / antagonists & inhibitors*
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Cyclic Nucleotide Phosphodiesterases, Type 7 / metabolism
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Disease Models, Animal*
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Dose-Response Relationship, Drug
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Drug Stability
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Enzyme Inhibitors / administration & dosage
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Humans
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Imidazoles / chemistry
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Imidazoles / pharmacology*
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / metabolism
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Male
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Mice
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Mice, Inbred C57BL
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Microsomes, Liver / chemistry
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Microsomes, Liver / metabolism
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Molecular Structure
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Parkinson Disease / drug therapy*
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Parkinson Disease / enzymology
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Parkinson Disease / metabolism
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Pyridones / chemistry
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Pyridones / pharmacology*
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Recombinant Proteins / antagonists & inhibitors
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Recombinant Proteins / metabolism
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Structure-Activity Relationship
Substances
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Enzyme Inhibitors
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Imidazoles
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Isoenzymes
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Pyridones
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Recombinant Proteins
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Cyclic Nucleotide Phosphodiesterases, Type 7
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PDE7A protein, human
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PDE7B protein, human