1ZGV

Thrombin in complex with an oxazolopyridine inhibitor 2

Summary for 1ZGV

• Entry DOI: 10.2210/pdb1zgv/pdb
• Related: 1ZGI
• Descriptor: Thrombin, Hirudin, N7-BUTYL-N2-(5-CHLORO-2-METHYLPHENYL)-5-METHYL[1,2,4]TRIAZOLO[1,5-A]PYRIMIDINE-2,7-DIAMINE, ... (4 entities in total)
• Functional Keywords: thrombin, thrombin inhibitor complex, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Secreted, extracellular space: P00734; Secreted: P28511
• Total number of polymer chains: 2
• Total formula weight: 34788.21

Authors

Deng, J.Z.,McMasters, D.R.,Rabbat, P.M.,Williams, P.D.,Coburn, C.A.,Yan, Y.,Kuo, L.C.,Lewis, S.D.,Lucas, B.J.,Krueger, J.A.,Strulovici, B.,Vacca, J.P.,Lyle, T.A.,Burgey, C.S. (deposition date: 2005-04-22, release date: 2005-09-27, Last modification date: 2024-11-20)

Primary citation

Deng, J.Z.,McMasters, D.R.,Rabbat, P.M.,Williams, P.D.,Coburn, C.A.,Yan, Y.,Kuo, L.C.,Lewis, S.D.,Lucas, B.J.,Krueger, J.A.,Strulovici, B.,Vacca, J.P.,Lyle, T.A.,Burgey, C.S.
Development of an oxazolopyridine series of dual thrombin/factor Xa inhibitors via structure-guided lead optimization.
Bioorg.Med.Chem.Lett., 15:4411-4416, 2005

PubMed Abstract: Thrombin-inhibitor X-ray crystal structures, in combination with the installation of binding elements optimized within the pyrazinone series of thrombin inhibitors, were utilized to transform a weak triazolopyrimidine lead into a series of potent oxazolopyridines. A modification intended to attenuate plasma protein binding (i.e., conversion of the P3 pyridine to a piperidine) conferred significant factor Xa activity to this series. Ultimately, these dual thrombin/factor Xa inhibitors demonstrated excellent in vitro and in vivo anticoagulant efficacy.

PubMed: 16137886
DOI: 10.1016/j.bmcl.2005.07.022

Experimental method

X-RAY DIFFRACTION (2.2 Å)