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PDBsum entry 5nib
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Rar-related orphan receptor-g (rorg)
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PDB id
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5nib
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References listed in PDB file
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Key reference
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Title
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Potent and orally bioavailable inverse agonists of rorγt resulting from structure-Based design.
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Authors
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F.Narjes,
Y.Xue,
S.Von berg,
J.Malmberg,
A.Llinas,
R.I.Olsson,
J.Jirholt,
H.Grindebacke,
A.Leffler,
N.Hossain,
M.Lepistö,
L.Thunberg,
H.Leek,
A.Aagaard,
J.Mcpheat,
E.L.Hansson,
E.Bäck,
S.Tångefjord,
R.Chen,
Y.Xiong,
G.Hongbin,
T.G.Hansson.
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Ref.
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J Med Chem, 2018,
61,
7796-7813.
[DOI no: ]
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PubMed id
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Abstract
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Retinoic acid receptor related orphan receptor γt (RORγt), has been identified
as the master regulator of TH17-cell function and development, making
it an attractive target for the treatment of autoimmune diseases by a
small-molecule approach. Herein, we describe our investigations on a series of
4-aryl-thienyl acetamides, which were guided by insights from X-ray cocrystal
structures. Efforts in targeting the cofactor-recruitment site from the 4-aryl
group on the thiophene led to a series of potent binders with nanomolar activity
in a primary human-TH17-cell assay. The observation of a DMSO
molecule binding in a subpocket outside the LBD inspired the introduction of an
acetamide into the benzylic position of these compounds. Hereby, a hydrogen-bond
interaction of the introduced acetamide oxygen with the backbone amide of Glu379
was established. This greatly enhanced the cellular activity of previously
weakly cell-active compounds. The best compounds combined potent inhibition of
IL-17 release with favorable PK in rodents, with compound 32 representing a
promising starting point for future investigations.
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