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.
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).
Quan
Mimi L
ML
Discovery Chemistry, Pharmaceutical Research Institute, Bristol-Myers Squibb Co., P.O. Box 5400, Princeton, New Jersey 08543-5400, USA. mimi.quan@bms.com
Lam
Patrick Y S
PY
Han
Qi
Q
Pinto
Donald J P
DJ
He
Ming Y
MY
Li
Renhua
R
Ellis
Christopher D
CD
Clark
Charles G
CG
Teleha
Christopher A
CA
Sun
Jung-Hui
JH
Alexander
Richard S
RS
Bai
Steve
S
Luettgen
Joseph M
JM
Knabb
Robert M
RM
Wong
Pancras C
PC
Wexler
Ruth R
RR
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism; D018938:Caco-2 Cells; D018360:Crystallography, X-Ray; D004285:Dogs; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D010539:Permeability; D011485:Protein Binding; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits; D013329:Structure-Activity Relationship; D013927:Thrombosis / Q000517:prevention & control
D001798:Blood Proteins; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D007093:Imidazoles; D007555:Isoxazoles; D011720:Pyrazoles; C500057:razaxaban