Antithrombotic and hemostatic effects of a small molecule factor XIa inhibitor in rats.
The effect of inhibiting activated blood coagulation factor XIa was determined in rat models of thrombosis and hemostasis. BMS-262084 is an irreversible and selective small molecule inhibitor of factor XIa with an IC(50) of 2.8 nM against human factor XIa. BMS-262084 doubled the activated thromboplastin time in human and rat plasma at 0.14 and 2.2 microM, respectively. Consistent with factor XIa inhibition, the prothrombin time was unaffected at up to 100 microM. BMS-262084 administered as an intravenous loading plus sustaining infusion was effective against FeCl(2)-induced thrombosis in both the vena cava and carotid artery. Maximum thrombus weight reductions of 97 and 73%, respectively (P<0.05), were achieved at a pretreatment dose of 12 mg/kg+12 mg/kg/h which increased the ex vivo activated thromboplastin time to 3.0 times control. This dose level also arrested growth of venous and arterial thrombi when administered after partial thrombus formation. BMS-262084 was most potent in FeCl(2)-induced venous thrombosis, decreasing thrombus weight 38% (P<0.05) at a threshold dose of 0.2 mg/kg+0.2 mg/kg/h. In contrast, doses of up to 24 mg/kg+24 mg/kg/h had no effect on either tissue factor-induced venous thrombosis or the ex vivo prothrombin time. Doses of up to 24 mg/kg+24 mg/kg/h also did not significantly prolong bleeding time provoked by either puncture of small mesenteric blood vessels, template incision of the renal cortex, or cuticle incision. These results demonstrate that pharmacologic inhibition of factor XIa achieves antithrombotic efficacy with minimal effects on provoked bleeding.
Schumacher
William A
WA
Discovery Biology, Bristol-Myers Squibb Company, Pennington, New Jersey 08534, USA. william.schumacher@bms.com
Seiler
Steven E
SE
Steinbacher
Thomas E
TE
Stewart
Anne B
AB
Bostwick
Jeffrey S
JS
Hartl
Karen S
KS
Liu
Eddie C
EC
Ogletree
Martin L
ML
D000818:Animals; D001384:Azetidines / Q000627:therapeutic use*; D002341:Carotid Artery Thrombosis / Q000188:drug therapy* / Q000503:physiopathology; D015945:Factor XIa / Q000037:antagonists & inhibitors*; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D006490:Hemostatics / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D010314:Partial Thromboplastin Time; D010879:Piperazines / Q000627:therapeutic use*; D011517:Prothrombin Time; D051381:Rats; D017207:Rats, Sprague-Dawley; D053802:Tryptases / Q000037:antagonists & inhibitors; D020246:Venous Thrombosis / Q000188:drug therapy* / Q000503:physiopathology
D001384:Azetidines; C467955:BMS-262084; D005343:Fibrinolytic Agents; D006490:Hemostatics; D010879:Piperazines; D015945:Factor XIa; D053802:Tryptases