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

• Published in: Journal of medicinal chemistry 2005-03, Vol.48 (6), p.1729-1744
• Main Authors: Quan, Mimi L, Lam, Patrick Y. S, Han, Qi, Pinto, Donald J. P, He, Ming Y, Li, Renhua, Ellis, Christopher D, Clark, Charles G, Teleha, Christopher A, Sun, Jung-Hui, Alexander, Richard S, Bai, Steve, Luettgen, Joseph M, Knabb, Robert M, Wong, Pancras C, Wexler, Ruth R
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Biological and medical sciences; Biological Availability; Blood Proteins - metabolism; Blood. Blood coagulation. Reticuloendothelial system; Caco-2 Cells; Crystallography, X-Ray; Dogs; Factor Xa Inhibitors; Fibrinolytic Agents - chemical synthesis; Fibrinolytic Agents - chemistry; Fibrinolytic Agents - pharmacology; Humans; Imidazoles - chemical synthesis; Imidazoles - chemistry; Imidazoles - pharmacology; Isoxazoles - chemical synthesis; Isoxazoles - chemistry; Isoxazoles - pharmacology; Medical sciences; Models, Molecular; Permeability; Pharmacology. Drug treatments; Protein Binding; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Rabbits; Structure-Activity Relationship; Thrombosis - prevention & control
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0497949

Modification of a series of pyrazole factor Xa inhibitors to incorporate an aminobenzisoxazole as the P1 ligand resulted in compounds with improved selectivity for factor Xa relative to trypsin and plasma kallikrein. Further optimization of the P4 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).