Summary
PDB 2J34 deposited: 2006-08-18 modified: 2009-02-24
Title CRYSTAL STRUCTURE OF A HUMAN FACTOR XA INHIBITOR COMPLEX
Authors Chan, C., Convery, M.A., Senger, S., Watson, N.S.
Method X-RAY DIFFRACTION
Structure factors resolution 2.01 rfactor 0.179 rfree 0.22
DPI 0.43 theoretical min: 0.18
Related PDB Entries 2J2U 2J38 2J94 2J95 4Y71 4Y76 4Y79 4Y7A 4Y7B
Citations

Factor Xa inhibitory activities for a series of N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}sulfonamides with different P1 groups are described. These data provide insight into binding interactions within the S1 primary specificity pocket; rationales are presented for the derived SAR on the basis of electronic interactions through crystal structures of fXa-ligand complexes and molecular modeling studies. A good correlation between in vitro anticoagulant activities with lipophilicity and the extent of human serum albumin binding is observed within this series of potent fXa inhibitors. Pharmacokinetic profiles in rat and dog, together with selectivity over other trypsin-like serine proteases, identified 1f as a candidate for further evaluation.

J. Med. Chem. 2007 Apr; 50(7):1546-1557 doi:10.1021/jm060870c

Torsional scans of sulfonamide S-C bonds in small model systems of a series of arylsulfonamide factor Xa inhibitors were performed in order to investigate if conformational effects can help to rationalise the observed SAR. Computational results were in good agreement with the experimental data indicating that the sulfonamide conformation plays an important role in determining the activity in this particular series of factor Xa inhibitors.

Bioorg.Med.Chem.Lett. 2006 Nov; 16(22):5731- doi:10.1016/J.BMCL.2006.08.092

Cross References
Database source Identifier Description
ChEMBL Document CHEMBL1142976
ChEMBL Document CHEMBL1139750
PubMed 17338508 JMCMAR
PubMed 16982192 BMCLE8
Biomolecule Structure Assembly Serial Assembly Type Conformational State Chains Ligands Atoms
2J34/1 2J34 1 dimer 0 2 2 2229