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Title
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3-Mercaptopropionic acids as efficacious inhibitors of activated thrombin activatable fibrinolysis inhibitor (TAFIa).
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Authors
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I.Islam,
J.Bryant,
K.May,
R.Mohan,
S.Yuan,
L.Kent,
J.Morser,
L.Zhao,
R.Vergona,
K.White,
M.Adler,
M.Whitlow,
B.O.Buckman.
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Ref.
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Bioorg Med Chem Lett, 2007,
17,
1349-1354.
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PubMed id
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Abstract
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A novel series of cyclic potent, selective, small molecule, thiol-based
inhibitors of activated thrombin activatable fibrinolysis inhibitor (TAFIa) and
the crystal structures of TAFIa inhibitors bound to porcine pancreatic
carboxypeptidase B are described. Three series of cyclic arginine and lysine
mimetic inhibitors vary significantly in their selectivity against other human
basic carboxypeptidases, carboxypeptidase N and carboxypeptidase B. (-)2a
displays TAFIa IC50 = 3 nM and 600-fold selectivity against CPN. Inhibition of
TAFIa with (rac)2a resulted in dose dependent acceleration of human plasma clot
lysis in vitro and was efficacious as an adjunct to tPA in an in vivo rabbit
jugular vein thrombolysis model.
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