Nonbenzamidine tetrazole derivatives as factor Xa inhibitors.
Factor Xa (fXa) is an important serine protease that holds the central position linking the intrinsic and extrinsic activation mechanisms in the blood coagulation cascade. Therefore, inhibition of fXa has potential therapeutic applications in the treatments of both arterial and venous thrombosis. Herein we describe a series of tetrazole fXa inhibitors containing benzamidine mimics as the P(1) substrate, of which the aminobenzisoxazole moiety was found to be the most potent benzamidine mimic. SR374 (12) inhibits fXa with a K(i) value of 0.35 nM and is very selective for fXa over 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
Woerner
Francis J
FJ
Alexander
Richard S
RS
Knabb
Robert M
RM
Lam
Patrick Y S
PY
Luettgen
Joseph M
JM
Wong
Pancras C
PC
Wright
Matthew R
MR
Wexler
Ruth R
RR
D000818:Animals; D001682:Biological Availability; D004285:Dogs; D065427:Factor Xa Inhibitors; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008958:Models, Molecular; D018716:Molecular Mimicry; D011487:Protein Conformation; D011817:Rabbits; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D013917:Thrombin / Q000037:antagonists & inhibitors; D014361:Trypsin Inhibitors / Q000494:pharmacology
D065427:Factor Xa Inhibitors; D015842:Serine Proteinase Inhibitors; D013777:Tetrazoles; D014361:Trypsin Inhibitors; D013917:Thrombin