Nonpeptide factor Xa inhibitors II. Antithrombotic evaluation in a rabbit model of electrically induced carotid artery thrombosis.
SK549 (mol. wt. 546 Da) is a synthetic, selective inhibitor of human coagulation factor Xa (fXa) (K(i) = 0.52 nM). This study compared the antithrombotic effects of SK549 and a series of benzamidine isoxazoline fXa inhibitors with aspirin, DuP 714 (a direct thrombin inhibitor), recombinant tick anticoagulant peptide, or heparin in a rabbit model of electrically induced carotid arterial thrombosis. Compounds were infused i.v. continuously from 60 min before electrical stimulation to the end of the experiment. Values of ED(50) (dose that increases the carotid blood flow to 50% of the control) were 0.12 micromol/kg/h for SK549, 0.56 micromol/kg/h for aspirin, 0.14 micromol/kg/h for DuP 714, 0.06 micromol/kg/h for recombinant tick anticoagulant peptide, and >100 U/kg/h for heparin. The EC(50) (plasma concentration that increased blood flow to 50% of the control) for SK549 was 97 nM. Unlike aspirin and heparin, SK549 was efficacious and, at 1.5 micromol/kg/h i.v. (n = 9), maintained carotid blood flow at 87 +/- 6% of control level for greater than 90 min. Unlike heparin, SK549 inhibited ex vivo fXa activity but not ex vivo thrombin activity. There was a highly significant correlation between K(i) (fXa) and ED(50) of a series of fXa inhibitors (r = 0. 85, P <.001). Therefore, these results suggest that SK549 is a novel, potent, and effective antithrombotic agent in a rabbit model of arterial thrombosis. It is likely that SK549 exerts its antithrombotic effect through selective inhibition of fXa. Furthermore, SK549 may be clinically useful for the prevention of arterial thrombosis.
Wong
P C
PC
Cardiovascular Diseases Research, DuPont Pharmaceuticals Company, Wilmington, Delaware, USA. pancras.c.wong@dupontpharma.com
Crain
E J
EJ
Knabb
R M
RM
Meade
R P
RP
Quan
M L
ML
Watson
C A
CA
Wexler
R R
RR
Wright
M R
MR
Slee
A M
AM
D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D001896:Boron Compounds / Q000494:pharmacology; D002341:Carotid Artery Thrombosis / Q000188:drug therapy*; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D006339:Heart Rate / Q000187:drug effects; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008855:Microscopy, Electron, Scanning; D009842:Oligopeptides / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D011817:Rabbits; D011994:Recombinant Proteins / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use*
D001896:Boron Compounds; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D007555:Isoxazoles; D009842:Oligopeptides; D011994:Recombinant Proteins; C120785:SK 549; D013777:Tetrazoles; C066061:acetylphenylalanyl-prolyl-boroarginine; D006493:Heparin; D001241:Aspirin