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PDBsum entry 1z71
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Hydrolase/hydrolase inhibitor
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PDB id
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1z71
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References listed in PDB file
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Key reference
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Title
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P2 pyridine n-Oxide thrombin inhibitors: a novel peptidomimetic scaffold.
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Authors
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P.G.Nantermet,
C.S.Burgey,
K.A.Robinson,
J.M.Pellicore,
C.L.Newton,
J.Z.Deng,
H.G.Selnick,
S.D.Lewis,
B.J.Lucas,
J.A.Krueger,
C.Miller-Stein,
R.B.White,
B.Wong,
D.R.Mcmasters,
A.A.Wallace,
J.J.Lynch,
Y.Yan,
Z.Chen,
L.Kuo,
S.J.Gardell,
J.A.Shafer,
J.P.Vacca,
T.A.Lyle.
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Ref.
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Bioorg Med Chem Lett, 2005,
15,
2771-2775.
[DOI no: ]
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PubMed id
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Abstract
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In this study, we have demonstrated that the critical hydrogen bonding motif of
the established 3-aminopyrazinone thrombin inhibitors can be effectively
mimicked by a 2-aminopyridine N-oxide. As this peptidomimetic core is more
resistant toward oxidative metabolism, it also overcomes the metabolic liability
associated with the pyrazinones. An optimization study of the P(1) benzylamide
delivered the potent thrombin inhibitor 21 (K(i) = 3.2 nM, 2xaPTT = 360 nM),
which exhibited good plasma levels and half-life after oral dosing in the dog
(C(max) = 2.6 microM, t(1/2) = 4.5 h).
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