Abstract
By utilizing structure-based drug design (SBDD) knowledge, a novel class of phosphodiesterase (PDE) 10A inhibitors was identified. The structure-based drug design efforts identified a unique "selectivity pocket" for PDE10A inhibitors, and interactions within this pocket allowed the design of highly selective and potent PDE10A inhibitors. Further optimization of brain penetration and drug-like properties led to the discovery of 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (PF-2545920). This PDE10A inhibitor is the first reported clinical entry for this mechanism in the treatment of schizophrenia.
MeSH terms
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Animals
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Antipsychotic Agents / chemical synthesis*
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Antipsychotic Agents / pharmacokinetics
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Antipsychotic Agents / pharmacology
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Avoidance Learning / drug effects
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Binding Sites
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Brain / metabolism
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Crystallography, X-Ray
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Dogs
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Female
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Humans
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Hydrogen Bonding
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In Vitro Techniques
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Macaca fascicularis
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Male
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Mice
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Mice, Knockout
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Microsomes, Liver / metabolism
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Models, Molecular*
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Molecular Structure
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Phosphoric Diester Hydrolases / chemistry
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Phosphoric Diester Hydrolases / genetics
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Phosphoric Diester Hydrolases / metabolism*
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Protein Binding
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Pyrazoles / chemical synthesis*
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Pyrazoles / pharmacokinetics
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Pyrazoles / pharmacology
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Quinolines / chemical synthesis*
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Quinolines / pharmacokinetics
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Quinolines / pharmacology
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Rats
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Rats, Sprague-Dawley
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Schizophrenia / drug therapy*
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Structure-Activity Relationship
Substances
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2-((4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)phenoxy)methyl)quinoline
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Antipsychotic Agents
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Pyrazoles
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Quinolines
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PDE10A protein, rat
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Pde10a protein, mouse
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Phosphoric Diester Hydrolases
Associated data
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PDB/3HQW
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PDB/3HQY
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PDB/3HR1