1ktt
From Proteopedia
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'''Thrombin inhibitor complex''' | '''Thrombin inhibitor complex''' | ||
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[[Category: Thrombin]] | [[Category: Thrombin]] | ||
[[Category: Nar, H.]] | [[Category: Nar, H.]] | ||
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Revision as of 20:09, 2 May 2008
Thrombin inhibitor complex
Overview
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.
About this Structure
1KTT is a Protein complex structure of sequences from Hirudo medicinalis and Homo sapiens. Full crystallographic information is available from OCA.
Reference
Structure-based design of novel potent nonpeptide thrombin inhibitors., Hauel NH, Nar H, Priepke H, Ries U, Stassen JM, Wienen W, J Med Chem. 2002 Apr 25;45(9):1757-66. PMID:11960487 Page seeded by OCA on Fri May 2 23:09:52 2008
