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Title
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Design, synthesis, and activity of 2,6-diphenoxypyridine-derived factor Xa inhibitors.
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Authors
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G.Phillips,
D.D.Davey,
K.A.Eagen,
S.K.Koovakkat,
A.Liang,
H.P.Ng,
M.Pinkerton,
L.Trinh,
M.Whitlow,
A.M.Beatty,
M.M.Morrissey.
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Ref.
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J Med Chem, 1999,
42,
1749-1756.
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PubMed id
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Abstract
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A novel series of 2,6-diphenoxypyridines has been designed to inhibit factor Xa,
a serine protease strategically located in the coagulation cascade. The
evolution from the photochemically unstable bisamidine (Z,Z)-BABCH to potent
bisamidine compounds with a pyridine heterocycle as the core scaffold has been
achieved. The most potent compound in the series, 6h, has a Ki for human factor
Xa of 12 nM. The selectivity of 6h against bovine trypsin and human thrombin was
greater than 90- and 1000-fold, respectively. Two proposed modes of binding of
6h to factor Xa are made based on the crystal structures of 6h by itself and of
6h bound to bovine trypsin.
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