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PDBsum entry 4fz7
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Transferase/transferase inhibitor
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PDB id
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4fz7
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References listed in PDB file
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Key reference
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Title
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Using ovality to predict nonmutagenic, Orally efficacious pyridazine amides as cell specific spleen tyrosine kinase inhibitors.
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Authors
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M.C.Lucas,
N.Bhagirath,
E.Chiao,
D.M.Goldstein,
J.C.Hermann,
P.Y.Hsu,
S.Kirchner,
J.J.Kennedy-Smith,
A.Kuglstatter,
C.Lukacs,
J.Menke,
L.Niu,
F.Padilla,
Y.Peng,
L.Polonchuk,
A.Railkar,
M.Slade,
M.Soth,
D.Xu,
P.Yadava,
C.Yee,
M.Zhou,
C.Liao.
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Ref.
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J Med Chem, 2014,
57,
2683-2691.
[DOI no: ]
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PubMed id
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Abstract
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Inhibition of spleen tyrosine kinase has attracted much attention as a mechanism
for the treatment of cancers and autoimmune diseases such as asthma, rheumatoid
arthritis, and systemic lupus erythematous. We report the structure-guided
optimization of pyridazine amide spleen tyrosine kinase inhibitors. Early
representatives of this scaffold were highly potent and selective but mutagenic
in an Ames assay. An approach that led to the successful identification of
nonmutagenic examples, as well as further optimization to compounds with reduced
cardiovascular liabilities is described. Select pharmacokinetic and in vivo
efficacy data are presented.
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