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PDBsum entry 1kts
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Hydrolase/hydrolase inhibitor
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PDB id
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1kts
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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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Structure-Based design of novel potent nonpeptide thrombin inhibitors.
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Authors
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N.H.Hauel,
H.Nar,
H.Priepke,
U.Ries,
J.M.Stassen,
W.Wienen.
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Ref.
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J Med Chem, 2002,
45,
1757-1766.
[DOI no: ]
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PubMed id
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Abstract
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The clinical syndromes of thromboembolism are evoked by an excessive stimulation
of the coagulation cascade. In this context, the serine protease thrombin plays
a key role. Considerable efforts have therefore been devoted to the discovery of
safe, orally active inhibitors of this enzyme. On the basis of the X-ray crystal
structure of the peptide-like thrombin inhibitor NAPAP complexed with bovine
thrombin, we have designed a new structural class of nonpeptidic inhibitors
employing a 1,2,5-trisubstituted benzimidazole as the central scaffold.
Supported by a series of X-ray structure analyses, we optimized the activity of
these compounds. Thrombin inhibition in the lower nanomolar range could be
achieved although the binding energy mainly results from nonpolar, hydrophobic
interactions. To improve in vivo potency, we increased the overall
hydrophilicity of the molecules by introducing carboxylate groups. The very
polar compound 24 (BIBR 953) exhibited the most favorable activity profile in
vivo. This zwitterionic molecule was converted into the double-prodrug 31 (BIBR
1048), which showed strong oral activity in different animal species. On the
basis of these results, 31 was chosen for clinical development.
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