Nonpeptide factor Xa inhibitors: I. Studies with SF303 and SK549, a new class of potent antithrombotics.
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 IC(50), respectively. A highly significant correlation was found between K(I) and IC(50) (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. ID(50) values for preventing arteriovenous shunt-induced thrombosis were 0.6 micromol/kg/h for SF303, 0.035 micromol/kg/h for SK549, 0.01 micromol/kg/h for recombinant tick anticoagulant peptide, 0.4 micromol/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 IC(50) of 0.062 microM. 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.
Wong
P C
PC
Cardiovascular Diseases Research, DuPont Pharmaceuticals Company, Wilmington, DE 19880-0400, USA. pancras.c.wong@dupontpharma.com
Quan
M L
ML
Crain
E J
EJ
Watson
C A
CA
Wexler
R R
RR
Knabb
R M
RM
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D001166:Arteriovenous Shunt, Surgical; D001777:Blood Coagulation / Q000187:drug effects*; D017985:Dalteparin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000494:pharmacology / Q000627:therapeutic use; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects*; D011422:Propionates / Q000494:pharmacology; D011817:Rabbits; D011994:Recombinant Proteins / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology*; D013777:Tetrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D013927:Thrombosis / Q000188:drug therapy*
C086910:(2S)-2-(4-(((3S)-1-acetimidoyl-3-pyrrolidinyl)oxy)phenyl)-3-(7-amidino-2-naphtyl)propanoic acid; D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D007555:Isoxazoles; D009281:Naphthalenes; D011422:Propionates; D011994:Recombinant Proteins; C403082:SF 303; C120785:SK 549; D013449:Sulfonamides; D013777:Tetrazoles; D006493:Heparin; D017985:Dalteparin