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PDBsum entry 1ta6
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Hydrolase/hydrolase inhibitor
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PDB id
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1ta6
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Design and synthesis of a series of potent and orally bioavailable noncovalent thrombin inhibitors that utilize nonbasic groups in the p1 position.
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Authors
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T.J.Tucker,
S.F.Brady,
W.C.Lumma,
S.D.Lewis,
S.J.Gardell,
A.M.Naylor-Olsen,
Y.Yan,
J.T.Sisko,
K.J.Stauffer,
B.J.Lucas,
J.J.Lynch,
J.J.Cook,
M.T.Stranieri,
M.A.Holahan,
E.A.Lyle,
E.P.Baskin,
I.W.Chen,
K.B.Dancheck,
J.A.Krueger,
C.M.Cooper,
J.P.Vacca.
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Ref.
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J Med Chem, 1998,
41,
3210-3219.
[DOI no: ]
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PubMed id
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Abstract
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As part of an ongoing effort to prepare therapeutically useful orally active
thrombin inhibitors, we have synthesized a series of compounds that utilize
nonbasic groups in the P1 position. The work is based on our previously reported
lead structure, compound 1, which was discovered via a resin-based approach to
varying P1. By minimizing the size and lipophilicity of the P3 group and by
incorporating hydrogen-bonding groups on the N-terminus or on the 2-position of
the P1 aromatic ring, we have prepared a number of derivatives in this series
that exhibit subnanomolar enzyme potency combined with good in vivo
antithrombotic and bioavailability profiles. The oxyacetic amide compound 14b
exhibited the best overall profile of in vitro and in vivo activity, and
crystallographic studies indicate a unique mode of binding in the thrombin
active site.
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