Abstract
We report on the discovery of two new lead series for the development of glucocorticoid receptor agonists. Firstly, the discovery of tetrahydronaphthalenes led to metabolically stable and dissociated compounds. Their binding mode to the glucocorticoid receptor could be elucidated through an X-ray structure. Closer inspection into the reaction path and analyses of side products revealed a new amino alcohol series also addressing the glucocorticoid receptor and demonstrating strong anti-inflammatory activity in vitro.
Keywords:
Amino alcohol; Glucocorticoid; SEGRA; Tetrahydronaphthalene; Transactivation; Transrepression.
Copyright © 2016 Elsevier Ltd. All rights reserved.
MeSH terms
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Amino Alcohols / chemistry
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Anti-Inflammatory Agents / chemistry*
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Anti-Inflammatory Agents / pharmacokinetics
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Anti-Inflammatory Agents / pharmacology
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Binding Sites
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Genes, Reporter
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Half-Life
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HeLa Cells
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Humans
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Hydrogen Bonding
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Inhibitory Concentration 50
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Microsomes, Liver / metabolism
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Molecular Docking Simulation
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Monocytes / cytology
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Monocytes / drug effects
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Monocytes / metabolism
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Protein Binding
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Receptors, Glucocorticoid / agonists*
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Receptors, Glucocorticoid / metabolism
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Structure-Activity Relationship
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Tetrahydronaphthalenes / chemistry*
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Tetrahydronaphthalenes / pharmacokinetics
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Tetrahydronaphthalenes / pharmacology
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Transcriptional Activation / drug effects
Substances
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Amino Alcohols
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Anti-Inflammatory Agents
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Receptors, Glucocorticoid
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Tetrahydronaphthalenes