Abstract
A series of novel 5-trans-hydroxyadamantan-2-yl-5,6,7,8-tetrahydropyrazolo[4,3-c]azepin-4(1H)-ones that inhibit 11beta-hydroxysteroid dehydrogenase type 1 are described. We discovered these 7-membered cyclic amide derivatives by introducing a distinctive linker through pharmacophore analysis of known ligands included in X-ray co-crystal structures. Further optimization using docking studies led to highly potent inhibitors 15b and 27, which furthermore showed the potent efficacy in in vivo studies.
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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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Amides / chemical synthesis
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Amides / chemistry*
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Amides / metabolism
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Animals
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Binding Sites
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Crystallography, X-Ray
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Drug Evaluation, Preclinical
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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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Hydrophobic and Hydrophilic Interactions
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Mice
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Molecular Docking Simulation
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Protein Binding
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Protein Structure, Tertiary
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Stereoisomerism
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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