Abstract
Utilizing structure-based virtual library design and scoring, a novel chimeric series of phosphodiesterase 10A (PDE10A) inhibitors was discovered by synergizing binding site interactions and ADME properties of two chemotypes. Virtual libraries were docked and scored for potential binding ability, followed by visual inspection to prioritize analogs for parallel and directed synthesis. The process yielded highly potent and selective compounds such as 16. New X-ray cocrystal structures enabled rational design of substituents that resulted in the successful optimization of physical properties to produce in vivo activity and to modulate microsomal clearance and permeability.
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
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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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Blood-Brain Barrier / metabolism
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Corpus Striatum / drug effects
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Corpus Striatum / metabolism
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Crystallography, X-Ray
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Cyclic GMP / metabolism
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Databases, Factual
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Drug Design
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Humans
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In Vitro Techniques
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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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Permeability
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Phosphodiesterase Inhibitors / chemical synthesis*
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Phosphodiesterase Inhibitors / pharmacokinetics
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Phosphodiesterase Inhibitors / pharmacology
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Phosphoric Diester Hydrolases / genetics
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Phosphoric Diester Hydrolases / metabolism*
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Protein Conformation
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Schizophrenia / drug therapy*
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Structure-Activity Relationship
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Antipsychotic Agents
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Phosphodiesterase Inhibitors
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PDE10A protein, human
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Pde10a protein, mouse
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Phosphoric Diester Hydrolases
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Cyclic GMP
Associated data
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OMIM/3QPN
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PDB/2O8H
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PDB/3HQW
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PDB/3QPO
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PDB/3QPP