Abstract
The design and development of a series of highly selective pyrrolidine carboxamide 11beta-HSD1 inhibitors are described. These compounds including PF-877423 demonstrated potent in vitro activity against both human and mouse 11beta-HSD1 enzymes. In an in vivo assay, PF-877423 inhibited the conversion of cortisone to cortisol. Structure guided optimization effort yielded potent and stable 11beta-HSD1 selective inhibitor 42.
2010 Elsevier Ltd. All rights reserved.
MeSH terms
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11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
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11-beta-Hydroxysteroid Dehydrogenase Type 1 / metabolism
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Adamantane / analogs & derivatives*
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Adamantane / chemical synthesis
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Adamantane / chemistry
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Adamantane / pharmacology
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Amides / chemical synthesis
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Amides / chemistry*
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Amides / pharmacology
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Animals
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacology
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Guinea Pigs
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Humans
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Hypoglycemic Agents / chemical synthesis
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Hypoglycemic Agents / chemistry*
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Hypoglycemic Agents / pharmacology
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Mice
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Microsomes, Liver / metabolism
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Pyrrolidines / chemical synthesis
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Pyrrolidines / chemistry*
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Pyrrolidines / pharmacology
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Structure-Activity Relationship
Substances
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Amides
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Enzyme Inhibitors
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Hypoglycemic Agents
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PF 877423
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Pyrrolidines
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11-beta-Hydroxysteroid Dehydrogenase Type 1
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pyrrolidine
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Adamantane