4NGA

Factor viia in complex with the inhibitor (2R)-2-[(1-aminoisoquinolin-6-yl)amino]-2-[3-ethoxy-4-(propan-2-yloxy)phenyl]-N-[2-(propan-2-ylsulfonyl)benzyl]ethanamide

Summary for 4NGA

• Entry DOI: 10.2210/pdb4nga/pdb
• Related: 4NG9
• Descriptor: Factor VIIa (Heavy Chain), Factor VIIa (Light Chain), (2R)-2-[(1-aminoisoquinolin-6-yl)amino]-2-[3-ethoxy-4-(propan-2-yloxy)phenyl]-N-[2-(propan-2-ylsulfonyl)benzyl]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
• Total number of polymer chains: 2
• Total formula weight: 35425.43

Authors

Wei, A.,Anumula, R. (deposition date: 2013-11-01, release date: 2014-01-08, Last modification date: 2023-09-20)

Primary citation

Zhang, X.,Jiang, W.,Jacutin-Porte, S.,Glunz, P.W.,Zou, Y.,Cheng, X.,Nirschl, A.H.,Wurtz, N.R.,Luettgen, J.M.,Rendina, A.R.,Luo, G.,Harper, T.M.,Wei, A.,Anumula, R.,Cheney, D.L.,Knabb, R.M.,Wong, P.C.,Wexler, R.R.,Priestley, E.S.
Design and Synthesis of Phenylpyrrolidine Phenylglycinamides As Highly Potent and Selective TF-FVIIa Inhibitors.
ACS Med Chem Lett, 5:188-192, 2014

PubMed Abstract: Inhibitors of the Tissue Factor/Factor VIIa (TF-FVIIa) complex are promising novel anticoagulants that show excellent efficacy and minimal bleeding in preclinical models. On the basis of a zwitterionic phenylglycine acylsulfonamide 1, a phenylglycine benzylamide 2 was shown to possess improved permeability and oral bioavailability. Optimization of the benzylamide, guided by X-ray crystallography, led to a potent TF-FVIIa inhibitor 18i with promising oral bioavailability, but promiscuous activity in an in vitro safety panel of receptors and enzymes. Introducing an acid on the pyrrolidine ring, guided by molecular modeling, resulted in highly potent, selective, and efficacious TF-FVIIa inhibitors with clean in vitro safety profile. The pyrrolidine acid 20 showed a moderate clearance, low volume of distribution, and a short t 1/2 in dog PK studies.

PubMed: 24900796
DOI: 10.1021/ml400453z

Experimental method

X-RAY DIFFRACTION (2.15 Å)