Abstract
Benzylamides of pentanedioic acid were identified as inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) by high-throughput screening. Optimisation to 2-adamantyl amides yielded inhibitors with single digit nanomolar IC(50)s on the 11beta-HSD1 human isoform. The hydroxy adamantyl amide lead compound was selective against 11beta-hydroxysteroid dehydrogenase type 2 (selectivity ratio >1000) and displayed good inhibition of 11beta-HSD1 (IC(50)<0.1microM) in a cellular model (3T3L1 adipocytes).
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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11-beta-Hydroxysteroid Dehydrogenase Type 2 / antagonists & inhibitors
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11-beta-Hydroxysteroid Dehydrogenase Type 2 / metabolism
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3T3-L1 Cells
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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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Drug Discovery
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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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Humans
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Mice
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Rats
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Structure-Activity Relationship
Substances
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Amides
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Enzyme Inhibitors
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11-beta-Hydroxysteroid Dehydrogenase Type 1
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11-beta-Hydroxysteroid Dehydrogenase Type 2