title: Discovery methodology for the development of direct factor VIIa inhibitors.
abstract: BACKGROUND
  Heparin and warfarin have historically been the only antithrombotics available. Recently, however, newer anticoagulants have been developed. Factor VIIa (fVIIa) inhibitors represent one of the new and potentially exciting classes of anticoagulants currently under development. Indeed, several methodologies have been used to develop fVIIa inhibitors.
  
  
  METHODS
  The authors highlight some of the methologies applied for the discovery of fVIIa inhibitors including phage display, isolation of endogenous peptides from hematophagous animals and the use of the 1,5-benzothiazepine molecular scaffolds and screens of large chemical libraries previously used to identify other serine protease inhibitors. Although these screens were intended to identify thrombin and factor Xa inhibitors, the compounds often had concomitant fVIIa activity. The authors also discuss the utilization of medical chemistry techniques for the discovery of these compounds.
  
  
  CONCLUSIONS
  FVIIa inhibitors represent a viable option for the development of new anticoagulants. There are theoretical advantages that fVIIa inhibitors may possess over existing anticoagulants and highly specific inhibitors that possess oral bioavailability and low bleeding risk may succeed.
authors.affiliation: University of Pittsburgh Medical Center, Heart and Vascular Institute Pittsburgh, Department of Cardiology , Scaife Hall, Suite B-571.3, 200 Lothrop Street, Pittsburgh, PA 15213 , USA +1 412 647 3429 ; +1 412 647 0481 ; henrybl@upmc.edu.
authors.forename: Brian L
authors.initials: BL
authors.lastname: Henry
authors.forename: Umesh R
authors.initials: UR
authors.lastname: Desai
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D001682:Biological Availability; D015195:Drug Design; D015942:Factor VIIa / Q000037:antagonists & inhibitors*; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D013841:Thiazepines / Q000737:chemistry / Q000494:pharmacology
chemical_list: C106746:1,5-benzothiazepine; D000925:Anticoagulants; D013841:Thiazepines; D015942:Factor VIIa
keywords: anticoagulants; coagulation; factor VIIa; small molecule inhibitors; tissue factor