4ISI

Structure of FACTOR VIIA in complex with the inhibitor (6S)-N-(4-CARBAMIMIDOYLBENZYL)-1-CHLORO-3-(CYCLOBUTYLAMINO)-8,8-DIETHYL-4-OXO-4,6,7,8-TETRAHYDROPYRROLO[1,2-A]PYRAZINE-6-CARBOXAMIDE

Summary for 4ISI

• Entry DOI: 10.2210/pdb4isi/pdb
• Related: 4ISH
• Descriptor: Factor VII heavy chain, Factor VII light chain, (6S)-N-(4-carbamimidoylbenzyl)-1-chloro-3-(cyclobutylamino)-8,8-diethyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxamide, ... (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: 34645.16

Authors

Wei, A. (deposition date: 2013-01-16, release date: 2013-02-27, Last modification date: 2024-11-06)

Primary citation

Zhang, X.,Glunz, P.W.,Jiang, W.,Schmitt, A.,Newman, M.,Barbera, F.A.,Bozarth, J.M.,Rendina, A.R.,Wei, A.,Wen, X.,Rossi, K.A.,Luettgen, J.M.,Wong, P.C.,Knabb, R.M.,Wexler, R.R.,Scott Priestley, E.
Design and synthesis of bicyclic pyrazinone and pyrimidinone amides as potent TF-FVIIa inhibitors.
Bioorg.Med.Chem.Lett., 23:1604-1607, 2013

PubMed Abstract: Bicyclic pyrazinone and pyrimidinone amides were designed and synthesized as potent TF-FVIIa inhibitors. SAR demonstrated that the S2 and S3 pockets of FVIIa prefer to bind small, lipophilic groups. An X-ray crystal structure of optimized compound 9b bound in the active site of FVIIa showed that the bicyclic scaffold provides 5 hydrogen bonding interactions in addition to projecting groups for interactions within the S1, S2 and S3 pockets. Compound 9b showed excellent FVIIa potency, good selectivity against FIXa, Xa, XIa and chymotrypsin, and good clotting activity.

PubMed: 23416003
DOI: 10.1016/j.bmcl.2013.01.094

Experimental method

X-RAY DIFFRACTION (1.94 Å)