Summary
PDB 1Z6E deposited: 2005-03-22 modified: 2011-07-13
Title Factor XA in complex with the inhibitor 1-(3'-amino-1,2-benzisoxazol-5'-yl)-n-(4-(2'-((dimethylamino)methyl)-1h-imidazol-1-yl)-2-fluorophenyl)-3-(trifluoromethyl)-1h-pyrazole-5-carboxamide (razaxaban; DPC906; BMS-561389)
Authors Alexander, R.S., Bai, S., Clark, C.G., Ellis, C.D., Han, Q., He, M.Y., Knabb, R.M., Lam, P.Y.S., Li, R., Luettgen, J.M., Pinto, D.J.P., Quan, M.L., Sun, J.-H., Teleha, C.A., Wexler, R.R., Wong, P.C.
Method X-RAY DIFFRACTION
Structure factors resolution 1.8 rfactor 0.219 rfree 0.26
DPI 0.40 theoretical min: 0.16
Citations

Modification of a series of pyrazole factor Xa inhibitors to incorporate an aminobenzisoxazole as the P(1) ligand resulted in compounds with improved selectivity for factor Xa relative to trypsin and plasma kallikrein. Further optimization of the P(4) moiety led to compounds with enhanced permeability and reduced protein binding. The SAR and pharmacokinetic profile of this series of compounds is described herein. These efforts culminated in 1-(3'-aminobenzisoxazol-5'-yl)-3-trifluoromethyl-N-[2-fluoro-4-[(2'-dimethylaminomethyl)imidazol-1-yl]phenyl]-1H-pyrazole-5-carboxyamide (11d), a potent, selective, and orally bioavailable inhibitor of factor Xa. On the basis of its excellent in vitro potency and selectivity profile, high free fraction in human plasma, good oral bioavailability, and in vivo efficacy in antithrombotic models, the HCl salt of this compound was selected for clinical development as razaxaban (DPC 906, BMS-561389).

J.Med.Chem. 2005 Mar; 48(6):1729-1744 doi:10.1021/jm0497949

Cross References
Database source Identifier Description
ChEMBL Document CHEMBL1145195
PubMed 15771420 JMCMAR
Biomolecule Structure Assembly Serial Assembly Type Conformational State Chains Ligands Atoms
1Z6E/1 1Z6E 1 dimer 0 2 1 2237