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PDBsum entry 6q7h
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Transcription
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PDB id
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6q7h
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References listed in PDB file
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Key reference
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Title
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Structure-Based and property-Driven optimization of n-Aryl imidazoles toward potent and selective oral rorγt inhibitors.
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Authors
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K.Hoegenauer,
J.Kallen,
E.Jiménez-Núñez,
R.Strang,
P.Ertl,
N.G.Cooke,
S.Hintermann,
M.Voegtle,
C.Betschart,
D.J.J.Mckay,
J.Wagner,
J.Ottl,
C.Beerli,
A.Billich,
J.Dawson,
K.Kaupmann,
M.Streiff,
N.Gobeau,
S.Harlfinger,
R.Stringer,
C.Guntermann.
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Ref.
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J Med Chem, 2019,
62,
10816-10832.
[DOI no: ]
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PubMed id
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Abstract
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Retinoic acid receptor-related orphan receptor gamma-t (RORγt) is considered to
be the master transcription factor for the development of Th17 cells that
produce proinflammatory cytokines such as IL-17A. Overproportionate Th17 cell
abundance is associated with the pathogenesis of many inflammatory conditions
including psoriasis. In a high-throughput fluorescence resonance energy transfer
(FRET) screen, we identified compound 1 as a hit with promising lipophilic
efficiency (LipE). Using structure-based drug design based on a number of X-ray
cocrystal structures, we morphed this hit class into potent imidazoles,
exemplified by compound 3. To improve the poor absorption, distribution,
metabolism, and excretion (ADME) properties of neutral imidazoles, we extended
our ligands with carboxylic acid substituents toward a polar, water-rich area of
the protein. This highly lipophilicity-efficient modification ultimately led to
the discovery of compound 14, a potent and selective inhibitor of RORγt
with good ADME properties and excellent in vivo pharmacokinetics. This compound
showed good efficacy in an in vivo delayed-type hypersensitivity pharmacology
model in rats.
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