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PDBsum entry 2gfs
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Signaling protein, transferase
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PDB id
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2gfs
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References listed in PDB file
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Key reference
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Title
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Discovery of s-[5-Amino-1-(4-Fluorophenyl)-1h-Pyrazol-4-Yl]-[3-(2,3-Dihydroxypropoxy)phenyl]methanone (ro3201195), An orally bioavailable and highly selective inhibitor of p38 map kinase.
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Authors
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D.M.Goldstein,
T.Alfredson,
J.Bertrand,
M.F.Browner,
K.Clifford,
S.A.Dalrymple,
J.Dunn,
J.Freire-Moar,
S.Harris,
S.S.Labadie,
J.La fargue,
J.M.Lapierre,
S.Larrabee,
F.Li,
E.Papp,
D.Mcweeney,
C.Ramesha,
R.Roberts,
D.Rotstein,
B.San pablo,
E.B.Sjogren,
O.Y.So,
F.X.Talamas,
W.Tao,
A.Trejo,
A.Villasenor,
M.Welch,
T.Welch,
P.Weller,
P.E.Whiteley,
K.Young,
S.Zipfel.
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Ref.
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J Med Chem, 2006,
49,
1562-1575.
[DOI no: ]
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PubMed id
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Abstract
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A novel class of highly selective inhibitors of p38 MAP kinase was discovered
from high throughput screening. The synthesis and optimization of a series of
5-amino-N-phenyl-1H-pyrazol-4-yl-3-phenylmethanones is described. An X-ray
crystal structure of this series bound in the ATP binding pocket of
unphosphorylated p38alpha established the presence of a unique hydrogen bond
between the exocyclic amine of the inhibitor and threonine 106 which likely
contributes to the selectivity for p38. The crystallographic information was
used to optimize the potency and physicochemical properties of the series. The
incorporation of the 2,3-dihydroxypropoxy moiety on the pyrazole scaffold
resulted in a compound with excellent drug-like properties including high oral
bioavailability. These efforts identified 63 (RO3201195) as an orally
bioavailable and highly selective inhibitor of p38 which was selected for
advancement into Phase I clinical trials.
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