1Z6E

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)

Summary for 1Z6E

• Entry DOI: 10.2210/pdb1z6e/pdb
• Descriptor: Coagulation factor X, 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, ... (4 entities in total)
• Functional Keywords: glycoprotein, hydrolase, serine protease, plasma, blood coagulation factor, protein inhibitor complex, calcium-binding, blood coagulation, cleavage on pair of basic residues, disulfide bond, egf-like domain
• Biological source: Homo sapiens (human); More
• Cellular location: Secreted: P00742 P00742
• Total number of polymer chains: 2
• Total formula weight: 32564.80

Authors

Alexander, R.S. (deposition date: 2005-03-22, release date: 2006-03-28, Last modification date: 2024-10-30)

Primary citation

Quan, M.L.,Lam, P.Y.S.,Han, Q.,Pinto, D.J.P.,He, M.Y.,Li, R.,Ellis, C.D.,Clark, C.G.,Teleha, C.A.,Sun, J.-H.,Alexander, R.S.,Bai, S.,Luettgen, J.M.,Knabb, R.M.,Wong, P.C.,Wexler, R.R.
Discovery of 1-(3'-aminobenzisoxazol-5'-yl)-3-trifluoromethyl-N-[2-fluoro-4-[(2'-dimethylaminomethyl)imidazol-1-yl]phenyl]-1H-pyrazole-5-carboxyamide hydrochloride (razaxaban), a highly potent, selective, and orally bioavailable factor Xa inhibitor.
J.Med.Chem., 48:1729-1744, 2005

PubMed Abstract: 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).

PubMed: 15771420
DOI: 10.1021/jm0497949

Experimental method

X-RAY DIFFRACTION (1.8 Å)