Aminobenzisoxazoles with biaryl P4 moieties as potent, selective, and orally bioavailable factor Xa inhibitors.
We have previously reported on a series of aminobenzisoxazoles as potent, selective, and orally bioavailable factor Xa inhibitors, which culminated in the discovery of razaxaban. Herein, we describe another approach to improve factor Xa inhibitory potency and pharmacokinetic profile by incorporating basic and water soluble functionalities on the terminal ring of the P4 biaryl group found in our earlier Xa inhibitors. This approach resulted in a series of potent, selective, and orally bioavailable factor Xa inhibitors.
Quan
Mimi L
ML
Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543, USA. mimi.quan@bms.com
Han
Qi
Q
Fevig
John M
JM
Lam
Patrick Y S
PY
Bai
Steve
S
Knabb
Robert M
RM
Luettgen
Joseph M
JM
Wong
Pancras C
PC
Wexler
Ruth R
RR
D000284:Administration, Oral; D001583:Benzoxazoles / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D065427:Factor Xa Inhibitors; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D001583:Benzoxazoles; D065427:Factor Xa Inhibitors; D015842:Serine Proteinase Inhibitors