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PDBsum entry 3h3c
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References listed in PDB file
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Key reference
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Title
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Sulfoximine-Substituted trifluoromethylpyrimidine analogs as inhibitors of proline-Rich tyrosine kinase 2 (pyk2) show reduced herg activity.
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Authors
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D.P.Walker,
M.P.Zawistoski,
M.A.Mcglynn,
J.C.Li,
D.W.Kung,
P.C.Bonnette,
A.Baumann,
L.Buckbinder,
J.A.Houser,
J.Boer,
A.Mistry,
S.Han,
L.Xing,
A.Guzman-Perez.
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Ref.
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Bioorg Med Chem Lett, 2009,
19,
3253-3258.
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PubMed id
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Abstract
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The synthesis, in vitro properties, and in vivo pharmacokinetics for a series of
sulfoximine-substituted trifluoromethylpyrimidines as inhibitors of proline-rich
tyrosine kinase, a target for the possible treatment of osteoporosis, are
described. These compounds were prepared as surrogates of the corresponding
sulfone compound 1. Sulfone 1 was an attractive PYK2 lead compound; however,
subsequent studies determined this compound possessed high dofetilide binding,
which is an early indicator of cardiovascular safety. Surprisingly, the
corresponding sulfoximine analogs displayed significantly lower dofetilide
binding, which, for N-methylsulfoximine (S)-14a, translated to lower activity in
a patch clamp hERG K(+) ion channel screen. In addition, compound (S)-14a shows
good oral exposure in a rat pharmacokinetic model.
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