dpc-423 and razaxaban

We have discovered that phenyltriazolinone is a novel and potent P1 moiety for coagulation factor Xa. X-ray structures of the inhibitors with a phenyltriazolinone in the P1 position revealed that the side chain of Asp189 has reoriented resulting in a novel S1 binding pocket which is larger in size to accommodate the phenyltriazolinone P1 substrate.

Topics: Anticoagulants; Crystallography, X-Ray; Drug Design; Factor Xa Inhibitors; Humans; Isoxazoles; Models, Molecular; Molecular Structure; Pyrazoles; Pyridones; Sulfones

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).

Topics: Administration, Oral; Animals; Biological Availability; Blood Proteins; Caco-2 Cells; Crystallography, X-Ray; Dogs; Factor Xa Inhibitors; Fibrinolytic Agents; Humans; Imidazoles; Isoxazoles; Models, Molecular; Permeability; Protein Binding; Pyrazoles; Rabbits; Structure-Activity Relationship; Thrombosis