Abstract
A forward chemical genetic approach was followed to discover new targets and lead compounds for Parkinson's disease (PD) treatment. By analysis of the cell protection produced by some small molecules, a diphenyl sulfide compound was revealed to be a new phosphodiesterase 7 (PDE7) inhibitor and identified as a new hit. This result allows us to confirm the utility of PDE7 inhibitors as a potential pharmacological treatment of PD. On the basis of these data, a diverse family of diphenyl sulfides has been developed and pharmacologically evaluated in the present work. Moreover, to gain insight into the safety of PDE7 inhibitors for human chronic treatment, we evaluated the new compounds in a surrogate emesis model, showing nonemetic effects.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Anesthesia / adverse effects
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / chemistry
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Blood-Brain Barrier / drug effects
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Cell Survival / drug effects
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Chemistry Techniques, Synthetic
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Cyclic Nucleotide Phosphodiesterases, Type 7 / antagonists & inhibitors*
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Cyclic Nucleotide Phosphodiesterases, Type 7 / chemistry
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Drug Evaluation, Preclinical / methods
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Humans
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Inhibitory Concentration 50
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Male
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Mice, Inbred Strains
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Models, Molecular
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Phosphodiesterase Inhibitors / chemical synthesis
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Phosphodiesterase Inhibitors / chemistry*
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Phosphodiesterase Inhibitors / pharmacology*
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Rats
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Structure-Activity Relationship
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Sulfides / chemistry
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Sulfides / pharmacology
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Vomiting / chemically induced
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Phosphodiesterase Inhibitors
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Sulfides
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Cyclic Nucleotide Phosphodiesterases, Type 7
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PDE7A protein, human