Abstract
The design, synthesis and structure activity relationship studies of a series of compounds from benzo[d]imidazo[5,1-b]thiazole scaffold as phosphodiesterase 10A (PDE10A) inhibitors are discussed. Several potent analogs with heteroaromatic substitutions (9a-d) were identified. The anticipated binding mode of these analogs was confirmed by performing the in silico docking experiments. Later, the heteroaromatics were substituted with saturated heteroalkyl groups which provided a tool compound 9e with excellent PDE10A activity, PDE selectivity, CNS penetrability and with favorable pharmacokinetic profile in rats. Furthermore, the compound 9e was shown to be efficacious in the MK-801 induced psychosis model and in the CAR model of psychosis.
Keywords:
Anti-psychotics; Conditioned Avoidance Response; MK-801; Phosphodiesterase 10A inhibitors; Schizophrenia.
Copyright © 2013 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Antipsychotic Agents / chemistry
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Antipsychotic Agents / pharmacokinetics
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Antipsychotic Agents / pharmacology
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Antipsychotic Agents / therapeutic use
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Disease Models, Animal
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Dizocilpine Maleate / toxicity
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Drug Evaluation, Preclinical
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Enzyme Activation / drug effects
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Female
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Half-Life
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Imidazoles / chemistry*
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Molecular Docking Simulation
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Phosphodiesterase Inhibitors / chemistry*
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Phosphodiesterase Inhibitors / pharmacokinetics
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Phosphodiesterase Inhibitors / pharmacology*
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Phosphodiesterase Inhibitors / therapeutic use
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Phosphoric Diester Hydrolases / chemistry*
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Phosphoric Diester Hydrolases / metabolism
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Psychotic Disorders / drug therapy
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Rats
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Rats, Sprague-Dawley
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Structure-Activity Relationship
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Thiazoles / chemistry*
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Thiazoles / pharmacokinetics
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Thiazoles / therapeutic use
Substances
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Antipsychotic Agents
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Imidazoles
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Phosphodiesterase Inhibitors
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Thiazoles
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Dizocilpine Maleate
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imidazole
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PDE10A protein, rat
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Phosphoric Diester Hydrolases