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PDBsum entry 2rg5
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References listed in PDB file
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Key reference
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Title
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Design, Synthesis, And anti-Inflammatory properties of orally active 4-(Phenylamino)-Pyrrolo[2,1-F][1,2,4]triazine p38alpha mitogen-Activated protein kinase inhibitors.
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Authors
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J.Hynes,
A.J.Dyckman,
S.Lin,
S.T.Wrobleski,
H.Wu,
K.M.Gillooly,
S.B.Kanner,
H.Lonial,
D.Loo,
K.W.Mcintyre,
S.Pitt,
D.R.Shen,
D.J.Shuster,
X.Yang,
R.Zhang,
K.Behnia,
H.Zhang,
P.H.Marathe,
A.M.Doweyko,
J.S.Tokarski,
J.S.Sack,
M.Pokross,
S.E.Kiefer,
J.A.Newitt,
J.C.Barrish,
J.Dodd,
G.L.Schieven,
K.Leftheris.
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Ref.
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J Med Chem, 2008,
51,
4-16.
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PubMed id
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Abstract
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A novel structural class of p38 mitogen-activated protein (MAP) kinase
inhibitors consisting of substituted 4-(phenylamino)-pyrrolo[2,1-
f][1,2,4]triazines has been discovered. An initial subdeck screen revealed that
the oxindole-pyrrolo[2,1- f][1,2,4]triazine lead 2a displayed potent enzyme
inhibition (IC 50 60 nM) and was active in a cell-based TNFalpha biosynthesis
inhibition assay (IC 50 210 nM). Replacement of the C4 oxindole with 2-methyl-5-
N-methoxybenzamide aniline 9 gave a compound with superior p38 kinase inhibition
(IC 50 10 nM) and moderately improved functional inhibition in THP-1 cells.
Further replacement of the C6 ester of the pyrrolo[2,1- f][1,2,4]triazine with
amides afforded compounds with increased potency, excellent oral
bioavailability, and robust efficacy in a murine model of acute inflammation
(murine LPS-TNFalpha). In rodent disease models of chronic inflammation,
multiple compounds demonstrated significant inhibition of disease progression
leading to the advancement of 2 compounds 11b and 11j into further preclinical
and toxicological studies.
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