Novel 2-methoxyacylhydrazones as potent, selective PDE10A inhibitors with activity in animal models of schizophrenia

A series of 2-methoxyacylhydrazones were optimized to yield compounds with high affinity for PDE10A. Several compounds demonstrated efficacy in animal models of schizophrenia, including conditioned avoidance response and a pro-psychotic phencyclidine hyperactivity model.

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2012-09, Vol.22 (17), p.5595-5599
Main Authors: Cutshall, Neil S., Onrust, Rene, Rohde, Alex, Gragerov, Sasha, Hamilton, Lauren, Harbol, Kevin, Shen, Hui-Rong, McKee, Shawn, Zuta, Charles, Gragerova, Galina, Florio, Vince, Wheeler, Thomas N., Gage, Jennifer L.
Format: Article
Language:English
Subjects:
Animals
Antipsychotic Agents - chemistry
Antipsychotic Agents - pharmacokinetics
Antipsychotic Agents - therapeutic use
Biological and medical sciences
Cognitive
Enzyme inhibitor
Hydrazide
Hydrazone
Hydrazones - chemistry
Hydrazones - pharmacokinetics
Hydrazones - therapeutic use
Medical sciences
Mice
PDE
PDE10
PDE10A
Pharmacology. Drug treatments
Phosphodiesterase
Phosphodiesterase Inhibitors - chemistry
Phosphodiesterase Inhibitors - pharmacokinetics
Phosphodiesterase Inhibitors - therapeutic use
Phosphoric Diester Hydrolases - metabolism
Schizophrenia
Schizophrenia - drug therapy
Schizophrenia - enzymology
Structure-Activity Relationship
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Description
Summary:A series of 2-methoxyacylhydrazones were optimized to yield compounds with high affinity for PDE10A. Several compounds demonstrated efficacy in animal models of schizophrenia, including conditioned avoidance response and a pro-psychotic phencyclidine hyperactivity model.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2012.07.007