Abstract
Modulation of cAMP levels has been linked to insulin secretion in preclinical animal models and in humans. The high expression of PDE-10A in pancreatic islets suggested that inhibition of this enzyme may provide the necessary modulation to elicit increased insulin secretion. Using an HTS approach, we have identified quinoline-based PDE-10A inhibitors as insulin secretagogues in vitro. Optimized compounds were evaluated in vivo where improvements in glucose tolerance and increases in insulin secretion were measured.
MeSH terms
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Drug Design
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Humans
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Insulin / metabolism*
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Insulin Secretion
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Islets of Langerhans / drug effects*
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Islets of Langerhans / metabolism
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Molecular Structure
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Phosphodiesterase Inhibitors / chemical synthesis
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Phosphodiesterase Inhibitors / pharmacology*
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Phosphoric Diester Hydrolases / drug effects
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Phosphoric Diester Hydrolases / metabolism*
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Quinolines / chemical synthesis
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Quinolines / chemistry
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Quinolines / pharmacology*
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Structure-Activity Relationship
Substances
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Insulin
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Phosphodiesterase Inhibitors
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Quinolines
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quinoline
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PDE10A protein, human
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Phosphoric Diester Hydrolases