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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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PDB id:
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| Name: |
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Transcription/agonist
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Title:
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Structure of rorgt in complex with a novel isoquinoline inverse agonist.
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Structure:
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Nuclear receptor ror-gamma. Chain: a, b. Synonym: nuclear receptor rzr-gamma,nuclear receptor subfamily 1 group f member 3,rar-related orphan receptor c,retinoid-related orphan receptor-gamma. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: rorc, nr1f3, rorg, rzrg. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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3.18Å
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R-factor:
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0.178
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R-free:
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0.227
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Authors:
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R.J.Skene,I.Hoffman
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Key ref:
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M.Kono
et al.
(2018).
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.
J Med Chem,
61,
2973-2988.
PubMed id:
DOI:
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Date:
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29-Nov-17
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Release date:
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21-Mar-18
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PROCHECK
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Headers
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References
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P51449
(RORG_HUMAN) -
Nuclear receptor ROR-gamma from Homo sapiens
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Seq:
Struc:
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518 a.a.
215 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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DOI no:
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J Med Chem
61:2973-2988
(2018)
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PubMed id:
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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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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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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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Links
