title: Factor XIa inhibitors: A review of the patent literature.
abstract: BACKGROUND
  Anticoagulants are the mainstay for prevention and/or treatment of thrombotic disorders. Each clinically used anticoagulant is associated with significant adverse consequences, especially bleeding. Factor XIa (FXIa), a key factor involved in the amplification of procoagulation signal, has been suggested as a major target for anticoagulant drug discovery because of reduced risk of bleeding.
  
  
  METHODS
  Our literature search uncovered dozens of industrial and academic patents on the discovery of novel FXIa/FXI inhibitors. Small peptidomimetics, sulfated glycosaminoglycan mimetics, polypeptides, antisense oligonucleotides, and monoclonal antibodies have been developed as inhibitors of FXIa. Although many agents are in early discovery/development phases, the activity and safety of a few have been evaluated in various animal models and in humans.
  
  
  CONCLUSIONS
  FXIa is a promising drug target for development of effective anticoagulants with limited bleeding complications. Literature reveals a major trend in the number of patent applications over the last three years. These inhibitors exploit different approaches for target inhibition. Allosteric modulation of FXIa and biosynthetic inhibition of FXI are mechanistically unique. Despite initial results in patients undergoing knee anthroplasty as with antisense oligonucleotides, major advances should be realized, particularly with respect to pharmacokinetics, for FXI/FXIa inhibitors to enter the clinic.
authors.affiliation: a Department of Medicinal Chemistry & Institute for Structural Biology , Drug Discovery and Development, Virginia Commonwealth University , Richmond , VA 23219 , USA.
authors.forename: Rami A
authors.initials: RA
authors.lastname: Al-Horani
authors.affiliation: a Department of Medicinal Chemistry & Institute for Structural Biology , Drug Discovery and Development, Virginia Commonwealth University , Richmond , VA 23219 , USA.
authors.forename: Umesh R
authors.initials: UR
authors.lastname: Desai
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D015195:Drug Design; D015945:Factor XIa / Q000037:antagonists & inhibitors*; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D010330:Patents as Topic; D013927:Thrombosis / Q000188:drug therapy
chemical_list: D000925:Anticoagulants; D015945:Factor XIa
keywords: FXI/FXIa; active site inhibitors; allosteric inhibitors; antisense oligonucleotides; drug discovery; enzyme inhibition; monoclonal antibodies; polypeptides; safe anticoagulant; thrombosis