Abstract
The identification of highly potent and orally active phenylpyrazines for the inhibition of PDE10A is reported. The new analogues exhibit subnanomolar potency for PDE10A, demonstrate high selectivity against all other members of the PDE family, and show desired druglike properties. Employing structure-based drug design approaches, we methodically explored two key regions of the binding pocket of the PDE10A enzyme to alter the planarity of the parent compound 1 and optimize its affinity for PDE10A. Bulky substituents at the C9 position led to elimination of the mutagenicity of 1, while a crucial hydrogen bond interaction with Glu716 markedly enhanced its potency and selectivity. A systematic assessment of the ADME and PK properties of the new analogues led to druglike development candidates. One of the more potent compounds, 96, displayed an IC(50) for PDE10A of 0.7 nM and was active in predictive antipsychotic animal models.
MeSH terms
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Administration, Oral
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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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Crystallography, X-Ray
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Cyclic AMP / chemistry
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Cyclic AMP / metabolism
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Cyclic GMP / metabolism
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Dogs
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Female
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Humans
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Hydrolysis
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Hyperkinesis / drug therapy
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In Vitro Techniques
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Isoenzymes / chemistry
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Isoenzymes / metabolism
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Ligands
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Male
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Mice
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Microsomes / metabolism
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Models, Molecular
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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 / chemistry
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Phosphoric Diester Hydrolases / metabolism*
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Protein Conformation
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Pyrazines / chemical synthesis*
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Pyrazines / pharmacokinetics
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Pyrazines / pharmacology
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Rats
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Rats, Sprague-Dawley
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Rats, Wistar
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Recombinant Proteins / chemistry
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Stereoisomerism
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Stereotyped Behavior / drug effects
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Structure-Activity Relationship
Substances
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Antipsychotic Agents
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Isoenzymes
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Ligands
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Phosphodiesterase Inhibitors
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Pyrazines
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Recombinant Proteins
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Cyclic AMP
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PDE10A protein, human
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Phosphoric Diester Hydrolases
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Cyclic GMP