2R2M

2-(2-Chloro-6-Fluorophenyl)Acetamides as Potent Thrombin Inhibitors

Summary for 2R2M

• Entry DOI: 10.2210/pdb2r2m/pdb
• Descriptor: Thrombin light chain, Thrombin heavy chain, Hirudin-3A, ... (5 entities in total)
• Functional Keywords: thrombin, acute phase, blood coagulation, cleavage on pair of basic residues, disease mutation, gamma-carboxyglutamic acid, glycoprotein, kringle, protease, secreted, serine protease, zymogen, protease inhibitor, serine protease inhibitor, sulfation, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Secreted, extracellular space: P00734 P00734; Secreted: P28507
• Total number of polymer chains: 3
• Total formula weight: 34711.00

Authors

Spurlino, J. (deposition date: 2007-08-27, release date: 2008-08-26, Last modification date: 2024-10-30)

Primary citation

Lee, L.,Kreutter, K.D.,Pan, W.,Crysler, C.,Spurlino, J.,Player, M.R.,Tomczuk, B.,Lu, T.
2-(2-Chloro-6-Fluorophenyl)Acetamides as Potent Thrombin Inhibitors
Bioorg.Med.Chem.Lett., 17:6266-6269, 2007

PubMed Abstract: 2-(2-Chloro-6-fluorophenyl)acetamides having 2,2-difluoro-2-aryl/heteroaryl-ethylamine P3 and oxyguanidine P1 substituents are potent thrombin inhibitors (K(i)=0.9-33.9 nM). 2-(5-Chloro-pyridin-2-yl)-2,2-difluoroethylamine was the best P3 substituent, yielding the most potent inhibitor (K(i)=0.7 nM). Replacing the P3 heteroaryl group with a phenyl ring or replacing the difluoro substitution with dimethyl or cyclopropyl groups in the linker reduced the affinity for thrombin significantly. The aminopyridine P1s also provided an increase in potency.

PubMed: 17889527
DOI: 10.1016/j.bmcl.2007.09.013

Experimental method

X-RAY DIFFRACTION (2.1 Å)