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PDBsum entry 3m37
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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 1-(2-Aminomethylphenyl)-3-Trifluoromethyl-N- [3-Fluoro-2'-(Aminosulfonyl)[1,1'-Biphenyl)]-4-Yl]-1h-Pyrazole-5-Carboxyamide (dpc602), A potent, Selective, And orally bioavailable factor xa inhibitor(1).
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Authors
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J.R.Pruitt,
D.J.Pinto,
R.A.Galemmo,
R.S.Alexander,
K.A.Rossi,
B.L.Wells,
S.Drummond,
L.L.Bostrom,
D.Burdick,
R.Bruckner,
H.Chen,
A.Smallwood,
P.C.Wong,
M.R.Wright,
S.Bai,
J.M.Luettgen,
R.M.Knabb,
P.Y.Lam,
R.R.Wexler.
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Ref.
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J Med Chem, 2003,
46,
5298-5315.
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PubMed id
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Abstract
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Factor Xa, a serine protease, is at the critical juncture between the intrinsic
and extrinsic pathways of the coagulation cascade. Inhibition of factor Xa has
the potential to provide effective treatment for both venous and arterial
thrombosis. We recently described a series of meta-substituted phenylpyrazoles
that are highly potent, selective, and orally bioavailable factor Xa inhibitors.
In this paper we report our efforts to further optimize the selectivity profile
of our factor Xa inhibitors with a series of ortho- and/or para-substituted
phenylpyrazole derivatives. The most potent compounds display sub-nanomolar
inhibition constants for factor Xa and show greater than 1000-fold selectivity
against other serine proteases. These compounds are also effective in a rabbit
model of arteriovenous shunt thrombosis. Optimization of this series led to the
preclinical development of DPC602, a 2-(aminomethyl)phenylpyrazole analogue, as
a highly potent, selective, and orally bioavailable factor Xa inhibitor.
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