Abstract
We report the discovery of potent benzamide inhibitors of 11beta-hydroxysteroid dehydrogenase (11beta-HSD1). The optimization and correlation of in vitro and in vivo metabolic stability will be described. Through modifications to our initial lead 2, we discovered pyridyl compound 13. This compound has a favorable pharmacokinetic profile across three species and showed a dose-dependent decrease in adipose 11beta-HSD1 activity in a monkey ex vivo pharmacodynamic model.
MeSH terms
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11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
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11-beta-Hydroxysteroid Dehydrogenase Type 1 / chemistry
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11-beta-Hydroxysteroid Dehydrogenase Type 1 / metabolism
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Administration, Oral
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Animals
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Benzamides / administration & dosage*
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Benzamides / chemical synthesis*
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Benzamides / chemistry
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Benzamides / metabolism
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Cell Line
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Crystallography, X-Ray
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Dogs
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Enzyme Inhibitors / administration & dosage*
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / metabolism
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Humans
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Macaca fascicularis
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Models, Animal
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Models, Molecular
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Molecular Structure
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Rats
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Structure-Activity Relationship
Substances
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Benzamides
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Enzyme Inhibitors
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benzamide
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11-beta-Hydroxysteroid Dehydrogenase Type 1