title: Antithrombotic potential of GW813893: a novel, orally active, active-site directed factor Xa inhibitor.
abstract: BACKGROUND
  Factor Xa (FXa) has been a target of considerable interest for drug development efforts aimed at suppressing thrombosis. In this report, a new orally active, small molecule, active-site directed FXa inhibitor, GW813893, has been profiled in a succession of in vitro and in vivo assays involved in its preclinical characterization as a potential antithrombotic therapeutic.
  
  
  METHODS
  In vitro profiling of GW813893 consisted of assessing its inhibitory potential against FXa and a broad panel of related and unrelated enzymes and receptors. Additionally, the FXa inhibition potential of GW813893 was assessed in prothrombinase and plasma-based clotting assays. In vivo characterization of GW813893 consisted of thrombosis studies in a rat inferior vena cava model, a rat carotid artery thrombosis model, and a rabbit jugular thrombosis model. Bleeding studies were conducted in a rat tail transection model. Ex vivo determinations of compound effects on FX and clotting activity were also undertaken.
  
  
  RESULTS
  GW813893 was more than 90-fold selective over all enzymes tested, and it inhibited FXa and prothrombinase activity with a Ki of 4.0 nM and 9.7 nM, respectively. In vivo, GW813893 concentration-dependently suppressed thrombotic activity in all models tested. The antithrombotic activity correlated with the suppression of plasma-based clotting activity and the inhibition of plasma FX activity (P < 0.02). Over the antithrombotic dose-range, an increased bleeding diathesis was not observed.
  
  
  CONCLUSIONS
  These experiments demonstrate that GW813893 is a potent, selective, orally active inhibitor of FXa. The data suggest that GW813893 has robust antithrombotic potential at doses that have no detectable hemostasis liability. Collectively, the profile suggests that GW813893 has the preclinical pharmacology underpinnings of an oral antithrombotic therapeutic.
authors.affiliation: GlaxoSmithkline, Cardiovascular & Urogenital Diseases Center of Excellence, King of Prussia, Pennsylvania, USA.
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Abboud
authors.forename: Saul J
authors.initials: SJ
authors.lastname: Needle
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Burns-Kurtis
authors.forename: Richard E
authors.initials: RE
authors.lastname: Valocik
authors.forename: Paul F
authors.initials: PF
authors.lastname: Koster
authors.forename: Augustin J
authors.initials: AJ
authors.lastname: Amour
authors.forename: Chuen
authors.initials: C
authors.lastname: Chan
authors.forename: David
authors.initials: D
authors.lastname: Brown
authors.forename: Laiq
authors.initials: L
authors.lastname: Chaudry
authors.forename: Ping
authors.initials: P
authors.lastname: Zhou
authors.forename: Angela
authors.initials: A
authors.lastname: Patikis
authors.forename: Champa
authors.initials: C
authors.lastname: Patel
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Pateman
authors.forename: Rob J
authors.initials: RJ
authors.lastname: Young
authors.forename: Nigel S
authors.initials: NS
authors.lastname: Watson
authors.forename: John R
authors.initials: JR
authors.lastname: Toomey
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001760:Bleeding Time; D001780:Blood Coagulation Tests; D002341:Carotid Artery Thrombosis / Q000188:drug therapy; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007601:Jugular Veins; D008297:Male; D011760:Pyrrolidinones / Q000494:pharmacology* / Q000627:therapeutic use; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D014682:Vena Cava, Inferior; D020246:Venous Thrombosis / Q000188:drug therapy
chemical_list: C532873:2-(5-chlorothien-2-yl)-N-(1-(1-methyl-2-(morpholin-4-yl)-2-oxoethyl)-2-oxopyrrolidin-3-yl)ethenesulfonamide; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D011760:Pyrrolidinones; D013449:Sulfonamides