4ISH

Structure of FACTOR VIIA in complex with the inhibitor BMS-593214 also known as 2'-[(6R,6AR,11BR)-2-CARBAMIMIDOYL-6,6A,7,11B-TETRAHYDRO-5H-INDENO[2,1-C]QUINOLIN-6-YL]-5'-HYDROXY-4'-METHOXYBIPHENYL-4-CARBOXYLIC ACID

Summary for 4ISH

• Entry DOI: 10.2210/pdb4ish/pdb
• Related: 4ISI
• Descriptor: Factor VII heavy chain, Factor VII light chain, 2'-[(6R,6aR,11bR)-2-carbamimidoyl-6,6a,7,11b-tetrahydro-5H-indeno[2,1-c]quinolin-6-yl]-5'-hydroxy-4'-methoxybiphenyl-4-carboxylic acid, ... (5 entities in total)
• Functional Keywords: glycoprotein, hydrolase, serine protease, plasma, blood coagulation factor, protein inhibitor complex, calcium-binding, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Secreted: P08709 P08709
• Total number of polymer chains: 2
• Total formula weight: 34679.72

Authors

Wei, A. (deposition date: 2013-01-16, release date: 2013-03-20, Last modification date: 2024-10-09)

Primary citation

Priestley, E.S.,De Lucca, I.,Zhou, J.,Zhou, J.,Saiah, E.,Stanton, R.,Robinson, L.,Luettgen, J.M.,Wei, A.,Wen, X.,Knabb, R.M.,Wong, P.C.,Wexler, R.R.
Discovery and gram-scale synthesis of BMS-593214, a potent, selective FVIIa inhibitor.
Bioorg.Med.Chem.Lett., 23:2432-2435, 2013

PubMed Abstract: A 6-amidinotetrahydroquinoline screening hit was driven to a structurally novel, potent, and selective FVIIa inhibitor through a combination of library synthesis and rational design. An efficient gram-scale synthesis of the active enantiomer BMS-593214 was developed, which required significant optimization of the key Povarov annulation. Importantly, BMS-593214 showed antithrombotic efficacy in a rabbit arterial thrombosis model. A crystal structure of BMS-593214 bound to FVIIa highlights key contacts with Asp 189, Lys 192, and the S2 pocket.

PubMed: 23478148
DOI: 10.1016/j.bmcl.2013.02.013

Experimental method

X-RAY DIFFRACTION (1.82 Å)