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PDBsum entry 1sl3
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Blood clotting,hydrolase/inhibitor
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PDB id
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1sl3
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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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Discovery and evaluation of potent p1 aryl heterocycle-Based thrombin inhibitors.
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Authors
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M.B.Young,
J.C.Barrow,
K.L.Glass,
G.F.Lundell,
C.L.Newton,
J.M.Pellicore,
K.E.Rittle,
H.G.Selnick,
K.J.Stauffer,
J.P.Vacca,
P.D.Williams,
D.Bohn,
F.C.Clayton,
J.J.Cook,
J.A.Krueger,
L.C.Kuo,
S.D.Lewis,
B.J.Lucas,
D.R.Mcmasters,
C.Miller-Stein,
B.L.Pietrak,
A.A.Wallace,
R.B.White,
B.Wong,
Y.Yan,
P.G.Nantermet.
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Ref.
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J Med Chem, 2004,
47,
2995-3008.
[DOI no: ]
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PubMed id
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Abstract
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In an effort to discover potent, clinically useful thrombin inhibitors, a rapid
analogue synthetic approach was used to explore the P(1) region. Various
benzylamines were coupled to a pyridine/pyrazinone P(2)-P(3) template. One
compound with an o-thiadiazole benzylic substitution was found to have a
thrombin K(i) of 0.84 nM. A study of ortho-substituted five-membered-ring
heterocycles was undertaken and subsequently demonstrated that the o-triazole
and tetrazole rings were optimal. Combination of these potent P(1) aryl
heterocycles with a variety of P(2)-P(3) groups produced a compound with an
extraordinary thrombin inhibitory activity of 1.4 pM. It is hoped that this
potency enhancement in P(1) will allow for more diversification in the P(2)-P(3)
region to ultimately address additional pharmacological concerns.
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