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PDBsum entry 3dt1
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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 highly selective and potent p38 inhibitors based on a phthalazine scaffold.
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Authors
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B.Herberich,
G.Q.Cao,
P.P.Chakrabarti,
J.R.Falsey,
L.Pettus,
R.M.Rzasa,
A.B.Reed,
A.Reichelt,
K.Sham,
M.Thaman,
R.P.Wurz,
S.Xu,
D.Zhang,
F.Hsieh,
M.R.Lee,
R.Syed,
V.Li,
D.Grosfeld,
M.H.Plant,
B.Henkle,
L.Sherman,
S.Middleton,
L.M.Wong,
A.S.Tasker.
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Ref.
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J Med Chem, 2008,
51,
6271-6279.
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PubMed id
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Abstract
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Investigations into the structure-activity relationships (SAR) of a series of
phthalazine-based inhibitors of p38 are described. These efforts originated from
quinazoline 1 and through rational design led to the development of a series of
orally bioavailable, potent, and selective inhibitors. Kinase selectivity was
achieved by exploiting a collection of interactions with p38alpha including
close contact to Ala157, occupation of the hydrophobic gatekeeper pocket, and a
residue flip with Gly110. Substitutions on the phthalazine influenced the
pharmacokinetic properties, of which compound 16 displayed the most desirable
profile. Oral dosing (0.03 mg/kg) of 16 in rats 1 h prior to LPS challenge gave
a >50% decrease in TNFalpha production.
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