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PDBsum entry 3m37
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* Residue conservation analysis
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Enzyme class:
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Chains A, L:
E.C.3.4.21.6
- coagulation factor Xa.
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Reaction:
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Preferential cleavage: Arg-|-Thr and then Arg-|-Ile bonds in prothrombin to form thrombin.
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J Med Chem
46:5298-5315
(2003)
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PubMed id:
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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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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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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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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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Y.K.Lee,
and
M.R.Player
(2011).
Developments in factor Xa inhibitors for the treatment of thromboembolic disorders.
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Med Res Rev,
31,
202-283.
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A.Sun,
J.J.Yoon,
Y.Yin,
A.Prussia,
Y.Yang,
J.Min,
R.K.Plemper,
and
J.P.Snyder
(2008).
Potent non-nucleoside inhibitors of the measles virus RNA-dependent RNA polymerase complex.
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J Med Chem,
51,
3731-3741.
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Y.Imaeda,
T.Miyawaki,
H.Sakamoto,
F.Itoh,
N.Konishi,
K.Hiroe,
M.Kawamura,
T.Tanaka,
and
K.Kubo
(2008).
Discovery of sulfonylalkylamides: A new class of orally active factor Xa inhibitors.
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Bioorg Med Chem,
16,
2243-2260.
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K.M.Bromfield,
N.S.Quinsey,
P.J.Duggan,
and
R.N.Pike
(2006).
Approaches to selective peptidic inhibitors of factor Xa.
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Chem Biol Drug Des,
68,
11-19.
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I.Gomez-Orellana
(2005).
Strategies to improve oral drug bioavailability.
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Expert Opin Drug Deliv,
2,
419-433.
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V.Rajagopal,
and
D.L.Bhatt
(2005).
Factor Xa inhibitors in acute coronary syndromes: moving from mythology to reality.
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J Thromb Haemost,
3,
436-438.
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
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Links
