Abstract
A new series of thiazolidine derivatives with an adamantyl group was synthesized and evaluated for their ability to inhibit 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1). Our initial compound 5a showed a weak inhibitory activity. Significant improvements in potency were achieved by substituent modification. The potent compound 8g (E) showed good in vitro inhibitory activity toward human 11β-HSD1, selectivity toward 11β-HSD2, metabolic stability, pharmacokinetic, and safety profile. Furthermore, this compound significantly inhibited 11β-HSD1 activity in rat and monkey models, and showed improved glycemic control in KKAy mice.
Copyright © 2010 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
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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Adamantane / analogs & derivatives*
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Adamantane / chemical synthesis
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Adamantane / chemistry*
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Adamantane / pharmacokinetics
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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 / pharmacokinetics
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Haplorhini
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Humans
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Mice
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Microsomes, Liver / metabolism
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Rats
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Structure-Activity Relationship
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Thiazolidines / chemical synthesis
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Thiazolidines / chemistry*
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Thiazolidines / pharmacokinetics
Substances
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Enzyme Inhibitors
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Thiazolidines
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11-beta-Hydroxysteroid Dehydrogenase Type 1
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11-beta-Hydroxysteroid Dehydrogenase Type 2
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Adamantane