Abstract
The identification of a new series of RORc inverse agonists is described. Comprehensive structure-activity relationship studies of this reversed sulfonamide series identified potent RORc inverse agonists in biochemical and cellular assays which were also selective against a panel of nuclear receptors. Our work has contributed a compound that may serve as a useful in vitro tool to delineate the complex biological pathways involved in signalling through RORc. An X-ray co-crystal structure of an analogue with RORc has also provided useful insights into the binding interactions of the new series.
Keywords:
IL-17; Inflammation; RORc; RORγ; RORγt; X-ray structure.
Copyright © 2014 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Binding Sites
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Cell Survival / drug effects
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Crystallography, X-Ray
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Cytokines / biosynthesis
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Drug Inverse Agonism
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HEK293 Cells
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Humans
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Leukocytes, Mononuclear / cytology
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Leukocytes, Mononuclear / drug effects
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Molecular Dynamics Simulation
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Nuclear Receptor Subfamily 1, Group F, Member 3 / agonists*
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Nuclear Receptor Subfamily 1, Group F, Member 3 / antagonists & inhibitors
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Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
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Protein Binding
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Protein Structure, Tertiary
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis
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Sulfonamides / chemistry*
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Sulfonamides / toxicity
Substances
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Cytokines
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Nuclear Receptor Subfamily 1, Group F, Member 3
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Sulfonamides