4JYU

Structure of factor VIIA in complex with the inhibitor (2R)-2-[(1-AMINOISOQUINOLIN-6-YL)AMINO]-2-[3-ETHOXY-4-(PROPAN-2-YLOXY)PHENYL]-N-(PHENYLSULFONYL)ETHANAMIDE

Summary for 4JYU

• Entry DOI: 10.2210/pdb4jyu/pdb
• Related: 4JYV
• Descriptor: Factor VII light chain, Factor VII heavy chain, (2R)-2-[(1-aminoisoquinolin-6-yl)amino]-2-[3-ethoxy-4-(propan-2-yloxy)phenyl]-N-(phenylsulfonyl)ethanamide, ... (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: 35461.42

Authors

Wei, A.,Anumula, R. (deposition date: 2013-04-01, release date: 2013-07-24, Last modification date: 2024-11-06)

Primary citation

Glunz, P.W.,Zhang, X.,Zou, Y.,Delucca, I.,Nirschl, A.H.,Cheng, X.,Weigelt, C.A.,Cheney, D.L.,Wei, A.,Anumula, R.,Luettgen, J.M.,Rendina, A.R.,Harpel, M.,Luo, G.,Knabb, R.,Wong, P.C.,Wexler, R.R.,Priestley, E.S.
Nonbenzamidine acylsulfonamide tissue factor-factor VIIa inhibitors.
Bioorg.Med.Chem.Lett., 23:5244-5248, 2013

PubMed Abstract: Aminoisoquinoline and isoquinoline groups have successfully replaced the more basic P1 benzamidine group of an acylsulfonamide factor VIIa inhibitor. Inhibitory activity was optimized by the identification of additional hydrophobic and hydrophilic P' binding interactions. The molecular details of these interactions were elucidated by X-ray crystallography and molecular modeling. We also show that decreasing the basicity of the P1 group results in improved oral bioavailability in this chemotype.

PubMed: 23845220
DOI: 10.1016/j.bmcl.2013.06.027

Experimental method

X-RAY DIFFRACTION (1.8 Å)