Abstract
A class of α-methyltryptamine sulfonamide glucocorticoid receptor (GR) modulators was optimized for agonist activity. The design of ligands was aided by molecular modeling, and key function-regulating pharmacophoric points were identified that are critical in achieving the desired agonist effect in cell based assays. Compound 27 was profiled in vitro and in vivo in models of inflammation. Analogs could be rapidly prepared in a parallel approach from aziridine building blocks.
Keywords:
Arylsulfonamide; Collagen induced arthritis; Glucocorticoid receptor; Glucocorticoids; Inflammation; Mineralocorticoid receptor; Nuclear hormone receptor; Progesterone receptor.
Copyright © 2013 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Anti-Inflammatory Agents / chemistry
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Anti-Inflammatory Agents / metabolism
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Anti-Inflammatory Agents / pharmacology
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Anti-Inflammatory Agents / therapeutic use
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Arthritis / chemically induced
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Arthritis / drug therapy
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Binding Sites
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Mice
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Molecular Docking Simulation
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Protein Binding / drug effects
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Protein Structure, Tertiary
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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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Sulfonamides / chemistry*
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Sulfonamides / metabolism
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Sulfonamides / pharmacology*
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Sulfonamides / therapeutic use
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Tryptamines / chemistry*
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Tryptamines / metabolism
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Tryptamines / pharmacology*
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Tryptamines / therapeutic use
Substances
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Anti-Inflammatory Agents
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Receptors, Glucocorticoid
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Sulfonamides
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Tryptamines