Factor XIa inhibitors: A review of the patent literature

ABSTRACT

Introduction: 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.

Areas covered: 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.

Expert opinion: 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.

KEY WORDS:

• drug discovery
• enzyme inhibition
• FXI/FXIa
• thrombosis
• safe anticoagulant
• active site inhibitors
• allosteric inhibitors
• polypeptides
• antisense oligonucleotides
• monoclonal antibodies

Article highlights

• FXIa, a serine protease in the intrinsic coagulation pathway, is a promising drug target for safer anticoagulation with respect to bleeding consequences.

• The past 3 years have realized a large number of industrial and academic patent applications describing new advances in the discovery of novel FXI/FXIa inhibitors.

• New agents include small peptidomimetics, sulfated glycosaminoglycan mimetics, polypeptides, antisense oligonucleotides, and monoclonal antibodies.

• Antithrombotic activity and safety of several FXI/FXIa inhibitors have been confirmed in arterial and venous animal models.

• Pharmacokinetics appears to be the major concern while developing these inhibitors for the clinical use.

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Declaration of interest

This work was supported by funding from the NIH through grants HL107152, HL090586 and HL128639 to UR Desai. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.