title: Pharmacological interruption of acute thrombus formation with minimal hemorrhagic complications by a small molecule tissue factor/factor VIIa inhibitor: comparison to factor Xa and thrombin inhibition in a nonhuman primate thrombosis model.
abstract: This study was designed to evaluate the antithrombotic efficacy and bleeding propensity of a selective, small-molecule inhibitor of tissue factor/factor VIIa (TF/VIIa) in comparison to small-molecule, selective inhibitors of factor Xa and thrombin in a nonhuman primate model of thrombosis. Acute, spontaneous thrombus formation was induced by electrolytic injury to the intimal surface of a femoral blood vessel, which results in thrombus propagation at the injured site. The TF/FVIIa inhibitor 3-amino-5-[1-[2-([4-[amino(imino)methyl]benzyl]amino)-2-oxoethyl]-3-chloro-5-(isopropylamino)-6-oxo-1,6-dihydropyrazin-2-yl]benzoic acid dihydrochloride (PHA-927F) was fully effective in prevention of thrombosis-induced vessel occlusion at a dose of 400 microg/kg/min, i.v., in the arterial vasculature (femoral artery). Neither the effective dose nor multiples up to 4.4-fold the effective arterial plasma concentration elicited any significant effect on bleeding time or blood loss from either the bleeding time site or the surgical (femoral isolation) site. Small-molecule inhibitors of factor Xa or thrombin were effective arterial antithrombotic agents; however, in contrast to the TF/FVIIa inhibitor, they both elicited substantial increases in bleeding propensity at the effective dose and at multiples of the effective plasma concentration. These data indicate that TF/VIIa inhibition effectively prevented arterial thrombosis with less impact on bleeding parameters than equivalent doses of factor Xa and thrombin inhibitors.
authors.affiliation: Pfizer Corporation, Department of Medicinal and Combinatorial Chemistry, St Louis, MO 63167, USA.
authors.forename: Osman D
authors.initials: OD
authors.lastname: Suleymanov
authors.forename: James A
authors.initials: JA
authors.lastname: Szalony
authors.forename: Anita K
authors.initials: AK
authors.lastname: Salyers
authors.forename: Rhonda M
authors.initials: RM
authors.lastname: LaChance
authors.forename: John J
authors.initials: JJ
authors.lastname: Parlow
authors.forename: Michael S
authors.initials: MS
authors.lastname: South
authors.forename: Rhonda S
authors.initials: RS
authors.lastname: Wood
authors.forename: Nancy S
authors.initials: NS
authors.lastname: Nicholson
mesh_terms: D062365:Aminobenzoates / Q000627:therapeutic use*; D000818:Animals; D001760:Bleeding Time; D004305:Dose-Response Relationship, Drug; D015942:Factor VIIa / Q000037:antagonists & inhibitors*; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D005542:Forearm / Q000502:physiology; D006439:Hemodynamics / Q000187:drug effects; D008252:Macaca fascicularis; D008297:Male; D011517:Prothrombin Time; D011719:Pyrazines / Q000627:therapeutic use*; D012965:Sodium Chloride; D013917:Thrombin / Q000037:antagonists & inhibitors; D013925:Thromboplastin / Q000037:antagonists & inhibitors; D013927:Thrombosis / Q000188:drug therapy*
chemical_list: C477641:3-amino-5-(1-(2-((4-(amino(imino)methyl)benzyl)amino)-2-oxoethyl)-3-chloro-5-(isopropylamino)-6-oxo-1,6-dihydropyrazin-2-yl)benzoic acid; D062365:Aminobenzoates; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D011719:Pyrazines; D012965:Sodium Chloride; D013925:Thromboplastin; D015942:Factor VIIa; D013917:Thrombin