Abstract
3-(Phenylcyclobutyl)-1,2,4-triazoles were identified as selective inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). These were active both in vitro and in an in vivo mouse pharmacodynamic (PD) model. Fluorine substitution of the cyclobutane ring improved the pharmacokinetic profile significantly. The synthesis and structure-activity relationships are presented.
MeSH terms
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11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
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Administration, Oral
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Animals
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Combinatorial Chemistry Techniques
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Cortisone / analysis
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Cortisone / blood
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Disease Models, Animal
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / pharmacokinetics
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Enzyme Inhibitors / pharmacology
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Humans
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Hydrocortisone / analysis
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Hydrocortisone / blood
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Mice
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Models, Molecular
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Molecular Structure
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Structure-Activity Relationship
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Triazoles / chemical synthesis*
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Triazoles / pharmacokinetics
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Triazoles / pharmacology*
Substances
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Enzyme Inhibitors
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Triazoles
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11-beta-Hydroxysteroid Dehydrogenase Type 1
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Cortisone
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Hydrocortisone