Abstract
A series of substituted 3,4-dihydro-2-quinolone glycogen phosphorylase inhibitors, which have potential as antidiabetic agents, is described. Initial members of the series showed good enzyme inhibitory potency but poor physical properties. Optimisation of the 1-substituent led to 2,3-dihydroxypropyl compounds which showed good in vitro potency and improved physical properties, together with good DMPK profiles and acute in vivo efficacy in a rat model. X-ray crystallographic data are presented, showing an unexpected variety of binding orientations at the dimer interface site.
MeSH terms
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Animals
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Biological Availability
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Blood Proteins / metabolism
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Caco-2 Cells
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Chemical Phenomena
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Chemistry, Physical
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Crystallography, X-Ray
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / pharmacology*
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Glycogen Phosphorylase / antagonists & inhibitors*
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Hepatocytes / drug effects
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Hepatocytes / enzymology
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Humans
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Hypoglycemic Agents / pharmacology*
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Indicators and Reagents
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Liver / enzymology
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Magnetic Resonance Spectroscopy
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Models, Molecular
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Molecular Conformation
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Muscle, Skeletal / enzymology
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Quinolines / chemical synthesis*
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Quinolines / pharmacology*
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Rabbits
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Rats
Substances
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Blood Proteins
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Enzyme Inhibitors
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Hypoglycemic Agents
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Indicators and Reagents
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Quinolines
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Glycogen Phosphorylase