Vol. 292, Issue 1, 351-357, January 2000

Nonpeptide Factor Xa Inhibitors: I. Studies with SF303 and SK549, a New Class of Potent Antithrombotics

Pancras C. Wong, Mimi L. Quan, Earl J., Crain, Carol A. Watson, Ruth R. Wexler and Robert M. Knabb

Cardiovascular Diseases Research (P.C.W., E.J.C., C.A.W., R.M.K.) and Chemical and Physical Sciences (M.L.Q., R.R.W.), DuPont Pharmaceuticals Company, Wilmington, Delaware

A series of benzamidine isoxazoline derivatives was evaluated for their inhibitory potency against purified human factor Xa (fXa) and in a rabbit model of arteriovenous shunt thrombosis for their antithrombotic activities, expressed as K_I and IC₅₀, respectively. A highly significant correlation was found between K_I and IC₅₀ (r = 0.93, P < .0001). The antithrombotic effects of SF303 [mol. wt. 536; K_I: fXa, 6.3 nM; thrombin, 3,100 nM; trypsin, 110 nM; tissue plasminogen activator >20,000 nM; plasmin, 2,500 nM] and SK549 [mol. wt. 546; K_I: fXa, 0.52 nM; thrombin, 400 nM; trypsin, 45 nM; tissue plasminogen activator >33,000 nM; plasmin, 890 nM] were compared with recombinant tick anticoagulant peptide [K_I(fXa) = 0.5 nM], DX-9065a [K_I(fXa) = 30 nM], and heparin or low molecular weight heparin (dalteparin) in a rabbit model of arteriovenous shunt thrombosis. ID₅₀ values for preventing arteriovenous shunt-induced thrombosis were 0.6 µmol/kg/h for SF303, 0.035 µmol/kg/h for SK549, 0.01 µmol/kg/h for recombinant tick anticoagulant peptide, 0.4 µmol/kg/h for DX-9065a, 21 U/kg/h for heparin, and 23 U/kg/h for low molecular weight heparin. SK549 produced a concentration-dependent antithrombotic effect with an IC₅₀ of 0.062 µM. To evaluate its potential oral efficacy, SK549 was given intraduodenally at a dose of 5 mg/kg; it produced a peak antithrombotic effect of 59 ± 4% with a duration of action greater than 6.7 h. Therefore, our study suggests that SF303, SK549, and their analogs represent a new class of synthetic fXa inhibitors that may be clinically useful as antithrombotic agents.