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PDBsum entry 4rfm
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Transferase/inhibitor
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PDB id
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4rfm
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References listed in PDB file
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Key reference
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Title
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Tetrahydroindazoles as interleukin-2 inducible t-Cell kinase inhibitors. Part ii. Second-Generation analogues with enhanced potency, Selectivity, And pharmacodynamic modulation in vivo.
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Authors
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J.D.Burch,
K.Barrett,
Y.Chen,
J.Devoss,
C.Eigenbrot,
R.Goldsmith,
M.H.Ismaili,
K.Lau,
Z.Lin,
D.F.Ortwine,
A.A.Zarrin,
P.A.Mcewan,
J.J.Barker,
C.Ellebrandt,
D.Kordt,
D.B.Stein,
X.Wang,
Y.Chen,
B.Hu,
X.Xu,
P.W.Yuen,
Y.Zhang,
Z.Pei.
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Ref.
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J Med Chem, 2015,
58,
3806-3816.
[DOI no: ]
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PubMed id
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Abstract
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The medicinal chemistry community has directed considerable efforts toward the
discovery of selective inhibitors of interleukin-2 inducible T-cell kinase
(ITK), given its role in T-cell signaling downstream of the T-cell receptor
(TCR) and the implications of this target for inflammatory disorders such as
asthma. We have previously disclosed a structure- and property-guided lead
optimization effort which resulted in the discovery of a new series of
tetrahydroindazole-containing selective ITK inhibitors. Herein we disclose
further optimization of this series that resulted in further potency
improvements, reduced off-target receptor binding liabilities, and reduced
cytotoxicity. Specifically, we have identified a correlation between the
basicity of solubilizing elements in the ITK inhibitors and off-target
antiproliferative effects, which was exploited to reduce cytotoxicity while
maintaining kinase selectivity. Optimized analogues were shown to reduce IL-2
and IL-13 production in vivo following oral or intraperitoneal dosing in mice.
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