2FEQ

orally active thrombin inhibitors

Summary for 2FEQ

• Entry DOI: 10.2210/pdb2feq/pdb
• Related: 1O0D
• Related PRD ID: PRD_000480 PRD_000612
• Descriptor: Thrombin light chain, Thrombin heavy chain, Decapeptide Hirudin Analogue, ... (5 entities in total)
• Functional Keywords: thrombin inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Secreted, extracellular space: P00734 P00734
• Total number of polymer chains: 3
• Total formula weight: 35855.94

Authors

Mack, H.,Baucke, D.,Hornberger, W.,Lange, U.E.W.,Hoeffken, H.W. (deposition date: 2005-12-16, release date: 2006-08-08, Last modification date: 2018-04-04)

Primary citation

Mack, H.,Baucke, D.,Hornberger, W.,Lange, U.E.W.,Seitz, W.,Hoeffken, H.W.
Orally active thrombin inhibitors. Part 1: optimization of the P1-moiety
Bioorg.Med.Chem.Lett., 16:2641-2647, 2006

PubMed Abstract: The synthesis and SAR of novel nanomolar thrombin inhibitors with the common backbone HOOC-CH(2)-d-cyclohexylalanyl-3,4-dehydroprolyl-NH-CH(2)-aryl-C(=NH)NH(2) are described together with their ecarin clotting time (ECT) prolongation as measure for thrombin inhibition ex vivo. The aryl P1-moiety mimicking the arginine part of the d-Phe-Pro-Arg derived thrombin inhibitors turned out to be a key component for in vitro potency and in vivo activity. Optimization of this part led to compounds with improved antithrombin activity in rats and dogs after oral administration compared to the recently launched anticoagulant melagatran.

PubMed: 16517159
DOI: 10.1016/j.bmcl.2006.02.040

Experimental method

X-RAY DIFFRACTION (2.44 Å)