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PDBsum entry 2ath
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Transcription
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PDB id
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2ath
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References listed in PDB file
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Key reference
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Title
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Novel indole-Based peroxisome proliferator-Activated receptor agonists: design, Sar, Structural biology, And biological activities.
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Authors
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N.Mahindroo,
C.F.Huang,
Y.H.Peng,
C.C.Wang,
C.C.Liao,
T.W.Lien,
S.K.Chittimalla,
W.J.Huang,
C.H.Chai,
E.Prakash,
C.P.Chen,
T.A.Hsu,
C.H.Peng,
I.L.Lu,
L.H.Lee,
Y.W.Chang,
W.C.Chen,
Y.C.Chou,
C.T.Chen,
C.M.Goparaju,
Y.S.Chen,
S.J.Lan,
M.C.Yu,
X.Chen,
Y.S.Chao,
S.Y.Wu,
H.P.Hsieh.
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Ref.
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J Med Chem, 2005,
48,
8194-8208.
[DOI no: ]
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PubMed id
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Abstract
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The synthesis and structure-activity relationship studies of novel indole
derivatives as peroxisome proliferator-activated receptor (PPAR) agonists are
reported. Indole, a drug-like scaffold, was studied as a core skeleton for the
acidic head part of PPAR agonists. The structural features (acidic head,
substitution on indole, and linker) were optimized first, by keeping
benzisoxazole as the tail part, based on binding and functional activity at
PPARgamma protein. The variations in the tail part, by introducing various
heteroaromatic ring systems, were then studied. In vitro evaluation led to
identification of a novel series of indole compounds with a benzisoxazole tail
as potent PPAR agonists with the lead compound 14 (BPR1H036) displaying an
excellent pharmacokinetic profile in BALB/c mice and an efficacious glucose
lowering activity in KKA(y) mice. Structural biology studies of 14 showed that
the indole ring contributes strong hydrophobic interactions with PPARgamma and
could be an important moiety for the binding to the protein.
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