Nonpeptide factor Xa inhibitors III: effects of DPC423, an orally-active pyrazole antithrombotic agent, on arterial thrombosis in rabbits.
DPC423 [1-[3-(aminomethyl)phenyl]-N-[3-fluoro-2'-(methylsulfonyl)[1,1'-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide] is a synthetic, competitive, and selective inhibitor of coagulation factor Xa (fXa) (K(i): 0.15 nM in humans, 0.3 nM in rabbit). The objective of this study was to compare effects of DPC423, enoxaparin (low-molecular-weight heparin), and argatroban (thrombin inhibitor) on arterial thrombosis and hemostasis in rabbit models of electrically induced carotid artery thrombosis and cuticle bleeding, respectively. Compounds were infused i.v. continuously from 60 min before artery injury or cuticle transection to the end of experiment. Carotid blood flow was used as a marker of antithrombotic effect. Antithrombotic ED(50) values were 0.4 mg/kg/h for enoxaparin (n = 6), 0.13 mg/kg/h for argatroban (n = 6), and 0.6 mg/kg/h for DPC423 (n = 12). DPC423 at the maximum antithrombotic dose increased activated partial thromboplastin time and prothrombin time (n = 6) by 1.8 +/- 0.07- and 1.8 +/- 0.13-fold, respectively, without changes in thrombin time and ex vivo thrombin activity. The antithrombotic effect of DPC423 was significantly correlated with its ex vivo anti-fXa activity (r = 0.86). DPC423 at 1, 3, and 10 mg/kg p.o. increased carotid blood flow (percent control) at 45 min to 10 +/- 4, 24 +/- 6, and 74 +/- 7, respectively (n = 6/group). Cuticle bleeding times (percent change over control) determined at the maximum antithrombotic dose were 88 +/- 12 for argatroban, 69 +/- 13 for heparin, 4 +/- 3 for enoxaparin, 5 +/- 4 for DPC423, and -3 +/- 2 for the vehicle (n = 5-6/group), suggesting dissociation of antithrombotic and bleeding time effects for DPC423 and enoxaparin. The combination of aspirin and DPC423 at ineffective antithrombotic doses produced significant antithrombotic effect. Therefore, these results suggest that DPC423 is a clinically useful oral anticoagulant for the prevention of arterial thrombosis.
Wong
Pancras C
PC
Cardiovascular Biology, Bristol-Myers Squibb Company, Wilmington, Delaware 19880-0400, USA. pancras.wong@bms.com
Crain
Earl J
EJ
Watson
Carol A
CA
Zaspel
Alverna M
AM
Wright
Matthew R
MR
Lam
Patrick Y
PY
Pinto
Donald J P
DJ
Wexler
Ruth R
RR
Knabb
Robert M
RM
D000284:Administration, Oral; D000818:Animals; D000990:Antithrombin III / Q000494:pharmacology* / Q000627:therapeutic use; D001241:Aspirin / Q000494:pharmacology; D001760:Bleeding Time; D001783:Blood Flow Velocity / Q000187:drug effects / Q000502:physiology; D002339:Carotid Arteries / Q000187:drug effects* / Q000502:physiology / Q000503:physiopathology; D002341:Carotid Artery Thrombosis / Q000188:drug therapy / Q000503:physiopathology; D004359:Drug Therapy, Combination; D005343:Fibrinolytic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D010314:Partial Thromboplastin Time; D010974:Platelet Aggregation / Q000187:drug effects; D011720:Pyrazoles / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D011817:Rabbits; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D013450:Sulfones / Q000494:pharmacology* / Q000627:therapeutic use; D013918:Thrombin Time
C421624:1-(3-(aminomethyl)phenyl)-N-(3-fluoro-2'-(methylsulfonyl)(1,1'-biphenyl)-4-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; D005343:Fibrinolytic Agents; D011720:Pyrazoles; D013450:Sulfones; D000990:Antithrombin III; D001241:Aspirin