5U6J

Factor VIIa in complex with the inhibitor 3-{[(2R)-17-ethyl-4-methyl-3,12-dioxo-7-[(propan-2-yl)sulfonyl]-13-oxa-4,11-diazatricyclo[14.2.2.1~6,10~]henicosa-1(18),6(21),7,9,16,19-hexaen-2-yl]amino}benzamide

Summary for 5U6J

• Entry DOI: 10.2210/pdb5u6j/pdb
• Descriptor: Coagulation factor VII Heavy Chain, Coagulation factor VII Light Chain, 3-{[(2R)-17-ethyl-4-methyl-3,12-dioxo-7-[(propan-2-yl)sulfonyl]-13-oxa-4,11-diazatricyclo[14.2.2.1~6,10~]henicosa-1(18),6(21),7,9,16,19-hexaen-2-yl]amino}benzamide, ... (7 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: 35335.31

Authors

Wei, A. (deposition date: 2016-12-08, release date: 2017-05-10, Last modification date: 2024-11-20)

Primary citation

Wurtz, N.R.,Parkhurst, B.L.,DeLucca, I.,Glunz, P.W.,Jiang, W.,Zhang, X.,Cheney, D.L.,Bozarth, J.M.,Rendina, A.R.,Wei, A.,Harper, T.,Luettgen, J.M.,Wu, Y.,Wong, P.C.,Seiffert, D.A.,Wexler, R.R.,Priestley, E.S.
Neutral macrocyclic factor VIIa inhibitors.
Bioorg. Med. Chem. Lett., 27:2650-2654, 2017

PubMed Abstract: Factor VIIa (FVIIa) inhibitors have shown strong antithrombotic efficacy in preclinical thrombosis models with limited bleeding liabilities. Discovery of potent, orally active FVIIa inhibitors has been largely unsuccessful due to the requirement of a basic P1 group to interact with Asp189 in the S1 binding pocket, limiting their membrane permeability. We have combined recently reported neutral P1 binding substituents with a highly optimized macrocyclic chemotype to produce FVIIa inhibitors with low nanomolar potency and enhanced permeability.

PubMed: 28460818
DOI: 10.1016/j.bmcl.2017.04.008

Experimental method

X-RAY DIFFRACTION (2.3 Å)