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PDBsum entry 2qbr
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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 optimization of protein tyrosine phosphatase 1b inhibitors: from the active site to the second phosphotyrosine binding site.
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Authors
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D.P.Wilson,
Z.K.Wan,
W.X.Xu,
S.J.Kirincich,
B.C.Follows,
D.Joseph-Mccarthy,
K.Foreman,
A.Moretto,
J.Wu,
M.Zhu,
E.Binnun,
Y.L.Zhang,
M.Tam,
D.V.Erbe,
J.Tobin,
X.Xu,
L.Leung,
A.Shilling,
S.Y.Tam,
T.S.Mansour,
J.Lee.
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Ref.
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J Med Chem, 2007,
50,
4681-4698.
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PubMed id
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Abstract
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Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of the insulin
and leptin receptor pathways and thus an attractive therapeutic target for
diabetes and obesity. Starting with a high micromolar lead compound,
structure-based optimization of novel PTP1B inhibitors by extension of the
molecule from the enzyme active site into the second phosphotyrosine binding
site is described. Medicinal chemistry, guided by X-ray complex structure and
molecular modeling, has yielded low nanomolar PTP1B inhibitors in an efficient
manner. Compounds from this chemical series were found to be actively
transported into hepatocytes. This active uptake into target tissues could be
one of the possible avenues to overcome the poor membrane permeability of PTP1B
inhibitors.
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Secondary reference #1
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Title
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Bicyclic and tricyclic thiophenes as protein tyrosine phosphatase 1b inhibitor
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Authors
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A.F.Moretto,
S.J.Kirincich,
W.X.Xu,
M.J.Smith,
Z.-K.Wan,
D.P.Wilson,
B.C.Follows,
E.Binnun,
D.Joseph-Mccarthy,
K.Foreman,
D.V.Erbe,
Y.-L.Zhang,
S.K.Tam,
S.Y.Tam,
J.Lee.
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Ref.
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bioorg med chem, 2006,
14,
2162.
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