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PDBsum entry 3byu
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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-Guided design of aminopyrimidine amides as potent, Selective inhibitors of lymphocyte specific kinase: synthesis, Structure-Activity relationships, And inhibition of in vivo t cell activation.
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Authors
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E.F.Dimauro,
J.Newcomb,
J.J.Nunes,
J.E.Bemis,
C.Boucher,
L.Chai,
S.C.Chaffee,
H.L.Deak,
L.F.Epstein,
T.Faust,
P.Gallant,
A.Gore,
Y.Gu,
B.Henkle,
F.Hsieh,
X.Huang,
J.L.Kim,
J.H.Lee,
M.W.Martin,
D.C.Mcgowan,
D.Metz,
D.Mohn,
K.A.Morgenstern,
A.Oliveira-Dos-Santos,
V.F.Patel,
D.Powers,
P.E.Rose,
S.Schneider,
S.A.Tomlinson,
Y.Y.Tudor,
S.M.Turci,
A.A.Welcher,
H.Zhao,
L.Zhu,
X.Zhu.
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Ref.
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J Med Chem, 2008,
51,
1681-1694.
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PubMed id
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Abstract
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The lymphocyte-specific kinase (Lck), a member of the Src family of cytoplasmic
tyrosine kinases, is expressed in T cells and natural killer (NK) cells. Genetic
evidence, including knockout mice and human mutations, demonstrates that Lck
kinase activity is critical for normal T cell development, activation, and
signaling. Selective inhibition of Lck is expected to offer a new therapy for
the treatment of T-cell-mediated autoimmune and inflammatory disease. With the
aid of X-ray structure-based analysis, aminopyrimidine amides 2 and 3 were
designed from aminoquinazolines 1, which had previously been demonstrated to
exhibit potent inhibition of Lck and T cell proliferation. In this report, we
describe the synthesis and structure-activity relationships of a series of novel
aminopyrimidine amides 3 possessing improved cellular potency and selectivity
profiles relative to their aminoquinazoline predecessors 1. Orally bioavailable
compound 13b inhibited the anti-CD3-induced production of interleukin-2 (IL-2)
in mice in a dose-dependent manner (ED 50 = 9.4 mg/kg).
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