Nonbenzamidine isoxazoline derivatives as factor Xa inhibitors.
Factor Xa (fXa) is an important serine protease in the blood coagulation cascade. Inhibition of fXa has emerged as an attractive target for potential therapeutic applications in the treatments of both arterial and venous thrombosis. Herein, we describe a series of non-benzamidine isoxazoline derivatives as fXa inhibitors. The chloroaniline group was found to be the most potent benzamidine mimic in this series. Chloroaniline 1 (ST368) has a K(i) value of 1.5 nM against fXa and is highly selective for fXa relative to thrombin and trypsin.
Quan
Mimi L
ML
Bristol-Myers Squibb Co., PO Box 80500, Wilmington, DE 19880-0500, USA. mimi.quan@bms.com
Ellis
Christopher D
CD
He
Ming Y
MY
Liauw
Ann Y
AY
Lam
Patrick Y S
PY
Rossi
Karen A
KA
Knabb
Robert M
RM
Luettgen
Joseph M
JM
Wright
Matthew R
MR
Wong
Pancras C
PC
Wexler
Ruth R
RR
D000818:Animals; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D007700:Kinetics; D008958:Models, Molecular; D011817:Rabbits
D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D007202:Indicators and Reagents; D007555:Isoxazoles