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PDBsum entry 4zjw
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Transcription
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PDB id
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4zjw
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References listed in PDB file
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Key reference
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Title
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Discovery of biaryl carboxylamides as potent rorγ inverse agonists.
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Authors
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J.Chao,
I.Enyedy,
K.Van vloten,
D.Marcotte,
K.Guertin,
R.Hutchings,
N.Powell,
H.Jones,
T.Bohnert,
C.C.Peng,
L.Silvian,
V.S.Hong,
K.Little,
D.Banerjee,
L.Peng,
A.Taveras,
J.L.Viney,
J.Fontenot.
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Ref.
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Bioorg Med Chem Lett, 2015,
25,
2991-2997.
[DOI no: ]
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PubMed id
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Abstract
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RORγt is a pivotal regulator of a pro-inflammatory gene expression program
implicated in the pathology of several major human immune-mediated diseases.
Evidence from mouse models demonstrates that genetic or pharmacological
inhibition of RORγ activity can block the production of pathogenic cytokines,
including IL-17, and convey therapeutic benefit. We have identified and
developed a biaryl-carboxylamide series of RORγ inverse agonists via a
structure based design approach. Co-crystal structures of compounds 16 and 48
supported the design approach and confirmed the key interactions with RORγ
protein; the hydrogen bonding with His479 was key to the significant improvement
in inverse agonist effect. The results have shown this is a class of potent and
selective RORγ inverse agonists, with demonstrated oral bioavailability in
rodents.
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