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PDBsum entry 6br2
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Transcription/agonist
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PDB id
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6br2
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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 [ cis-3-({(5 r)-5-[(7-Fluoro-1,1-Dimethyl-2,3-Dihydro-1 h-Inden-5-Yl)carbamoyl]-2-Methoxy-7,8-Dihydro-1,6-Naphthyridin-6(5 h)-Yl}carbonyl)cyclobutyl]acetic acid (tak-828f) as a potent, Selective, And orally available novel retinoic acid receptor-Related orphan receptor γt inverse agonist.
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Authors
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M.Kono,
A.Ochida,
T.Oda,
T.Imada,
Y.Banno,
N.Taya,
S.Masada,
T.Kawamoto,
K.Yonemori,
Y.Nara,
Y.Fukase,
T.Yukawa,
H.Tokuhara,
R.Skene,
B.C.Sang,
I.D.Hoffman,
G.P.Snell,
K.Uga,
A.Shibata,
K.Igaki,
Y.Nakamura,
H.Nakagawa,
N.Tsuchimori,
M.Yamasaki,
J.Shirai,
S.Yamamoto.
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Ref.
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J Med Chem, 2018,
61,
2973-2988.
[DOI no: ]
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PubMed id
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Abstract
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A series of tetrahydronaphthyridine derivatives as novel RORγt inverse agonists
were designed and synthesized. We reduced the lipophilicity of
tetrahydroisoquinoline compound 1 by replacement of the trimethylsilyl group and
SBDD-guided scaffold exchange, which successfully afforded compound 7 with a
lower log D value and tolerable in vitro activity. Consideration of LLE values
in the subsequent optimization of the carboxylate tether led to the discovery of
[ cis-3-({(5 R)-5-[(7-fluoro-1,1-dimethyl-2,3-dihydro-1
H-inden-5-yl)carbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5
H)-yl}carbonyl)cyclobutyl]acetic acid, TAK-828F (10), which showed potent RORγt
inverse agonistic activity, excellent selectivity against other ROR isoforms and
nuclear receptors, and a good pharmacokinetic profile. In animal studies, oral
administration of compound 10 exhibited robust and dose-dependent inhibition of
IL-17A cytokine expression in a mouse IL23-induced gene expression assay.
Furthermore, development of clinical symptoms in a mouse experimental autoimmune
encephalomyelitis model was significantly reduced. Compound 10 was selected as a
clinical compound for the treatment of Th17-driven autoimmune diseases.
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