4ZXX

FACTOR VIIA IN COMPLEX WITH THE INHIBITOR N-{3-[(2R)-1-{(2R)-2-[(1-aminoisoquinolin-6-yl)amino]-2-phenylacetyl}pyrrolidin-2-yl]-4-(propan-2-ylsulfonyl)phenyl}acetamide

Summary for 4ZXX

• Entry DOI: 10.2210/pdb4zxx/pdb
• Related: 4ZXY
• Descriptor: Coagulation factor VIIa heavy chain, Coagulation factor VIIa light chain, N-{3-[(2R)-1-{(2R)-2-[(1-aminoisoquinolin-6-yl)amino]-2-phenylacetyl}pyrrolidin-2-yl]-4-(propan-2-ylsulfonyl)phenyl}acetamide, ... (6 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: 35048.07

Authors

Wei, A. (deposition date: 2015-05-20, release date: 2015-07-22, Last modification date: 2024-10-23)

Primary citation

Priestley, E.S.,Cheney, D.L.,DeLucca, I.,Wei, A.,Luettgen, J.M.,Rendina, A.R.,Wong, P.C.,Wexler, R.R.
Structure-Based Design of Macrocyclic Coagulation Factor VIIa Inhibitors.
J.Med.Chem., 58:6225-6236, 2015

PubMed Abstract: On the basis of a crystal structure of a phenylpyrrolidine lead and subsequent molecular modeling results, we designed and synthesized a novel series of macrocyclic FVIIa inhibitors. The optimal 16-membered macrocycle was 60-fold more potent than an acyclic analog. Further potency optimization by incorporation of P1' alkyl sulfone and P2 methyl groups provided a macrocycle with TF/FVIIa Ki = 1.6 nM, excellent selectivity against a panel of seven serine proteases, and FVII-deficient prothrombin time EC2x = 1.2 μM. Discovery of this potent, selective macrocyclic scaffold opens new possibilities for the development of orally bioavailable FVIIa inhibitors.

PubMed: 26151189
DOI: 10.1021/acs.jmedchem.5b00788

Experimental method

X-RAY DIFFRACTION (2.6 Å)