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PDBsum entry 5k5n
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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 a highly selective glycogen synthase kinase-3 inhibitor (pf-04802367) that modulates tau phosphorylation in the brain: translation for pet neuroimaging.
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Authors
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S.H.Liang,
J.M.Chen,
M.D.Normandin,
J.S.Chang,
G.C.Chang,
C.K.Taylor,
P.Trapa,
M.S.Plummer,
K.S.Para,
E.L.Conn,
L.Lopresti-Morrow,
L.F.Lanyon,
J.M.Cook,
K.E.Richter,
C.E.Nolan,
J.B.Schachter,
F.Janat,
Y.Che,
V.Shanmugasundaram,
B.A.Lefker,
B.E.Enerson,
E.Livni,
L.Wang,
N.J.Guehl,
D.Patnaik,
F.F.Wagner,
R.Perlis,
E.B.Holson,
S.J.Haggarty,
G.El fakhri,
R.G.Kurumbail,
N.Vasdev.
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Ref.
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Angew Chem Int Ed Engl, 2016,
55,
9601-9605.
[DOI no: ]
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PubMed id
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Abstract
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Glycogen synthase kinase-3 (GSK-3) regulates multiple cellular processes in
diabetes, oncology, and neurology.
N-(3-(1H-1,2,4-triazol-1-yl)propyl)-5-(3-chloro-4-methoxyphenyl)oxazole-4-carboxamide
(PF-04802367 or PF-367) has been identified as a highly potent inhibitor, which
is among the most selective antagonists of GSK-3 to date. Its efficacy was
demonstrated in modulation of tau phosphorylation in vitro and in vivo.
Whereas the kinetics of PF-367 binding in brain tissues are too fast for an
effective therapeutic agent, the pharmacokinetic profile of PF-367 is ideal for
discovery of radiopharmaceuticals for GSK-3 in the central nervous system. A
(11) C-isotopologue of PF-367 was synthesized and preliminary PET imaging
studies in non-human primates confirmed that we have overcome the two major
obstacles for imaging GSK-3, namely, reasonable brain permeability and
displaceable binding.
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