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PDBsum entry 2ofu
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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 2-Aminopyrimidine carbamates as potent and orally active inhibitors of lck: synthesis, Sar, And in vivo antiinflammatory activity.
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Authors
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M.W.Martin,
J.Newcomb,
J.J.Nunes,
D.C.Mcgowan,
D.M.Armistead,
C.Boucher,
J.L.Buchanan,
W.Buckner,
L.Chai,
D.Elbaum,
L.F.Epstein,
T.Faust,
S.Flynn,
P.Gallant,
A.Gore,
Y.Gu,
F.Hsieh,
X.Huang,
J.H.Lee,
D.Metz,
S.Middleton,
D.Mohn,
K.Morgenstern,
M.J.Morrison,
P.M.Novak,
A.Oliveira-Dos-Santos,
D.Powers,
P.Rose,
S.Schneider,
S.Sell,
Y.Tudor,
S.M.Turci,
A.A.Welcher,
R.D.White,
D.Zack,
H.Zhao,
L.Zhu,
X.Zhu,
C.Ghiron,
P.Amouzegh,
M.Ermann,
J.Jenkins,
D.Johnston,
S.Napier,
E.Power.
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Ref.
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J Med Chem, 2006,
49,
4981-4991.
[DOI no: ]
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PubMed id
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Abstract
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The lymphocyte-specific kinase (Lck) is a cytoplasmic tyrosine kinase of the Src
family expressed in T cells and NK cells. Genetic evidence in both mice and
humans demonstrates that Lck kinase activity is critical for signaling mediated
by the T cell receptor (TCR), which leads to normal T cell development and
activation. A small molecule inhibitor of Lck is expected to be useful in the
treatment of T cell-mediated autoimmune and inflammatory disorders and/or organ
transplant rejection. In this paper, we describe the synthesis,
structure-activity relationships, and pharmacological characterization of
2-aminopyrimidine carbamates, a new class of compounds with potent and selective
inhibition of Lck. The most promising compound of this series,
2,6-dimethylphenyl
2-((3,5-bis(methyloxy)-4-((3-(4-methyl-1-piperazinyl)propyl)oxy)phenyl)amino)-4-pyrimidinyl(2,4-bis(methyloxy)phenyl)carbamate
(43) exhibits good activity when evaluated in in vitro assays and in an in vivo
model of T cell activation.
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