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PDBsum entry 6dup
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Nuclear protein
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PDB id
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6dup
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References listed in PDB file
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Key reference
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Title
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Amelioration of pxr-Mediated cyp3a4 induction by mglur2 modulators.
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Authors
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R.J.Vaz,
Y.Li,
V.Chellaraj,
S.Reiling,
T.Kuntzweiler,
D.Yang,
H.Shen,
J.D.Batchelor,
Y.Zhang,
X.Chen,
L.R.Mclean,
R.Kosley.
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Ref.
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Bioorg Med Chem Lett, 2018,
28,
3194-3196.
[DOI no: ]
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PubMed id
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Abstract
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This work describes the rational amelioration of Cytochrome P450 4/5 (CYP3A4/5)
induction through the Pregnane-X Receptor (PXR) pathway in a series of compounds
that modulate the metabotropic glutamate Receptor 2 (mGluR2) via an allosteric
mechanism. The compounds were initially shown to induce CYP3A4/5 via the
gold-standard induction assay measured in primary human hepatocytes. This was
followed up by testing the compounds in a PXR assay which correlated well with
the assay in primary cells. Further, one of the compounds was crystallized with
PXR (pdb code 6DUP). Analysis of this co-crystal structure, together with
previously published PXR co-crystal structures, lead to modification ideas. The
compounds synthesized based on these ideas were shown not to be CYP3A4/5
inducers. The mGluR2 activity of the resulting compounds was maintained.
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