Title

Recent Advances in the Discovery and Development of Factor XI/XIa Inhibitors.

Funding Source

National Institutes of Health, National Institute of General Medical Sciences, National Institute on Minority Health and Health Disparities,

Grant Number

5G12MD007595, 5 P20 GM103424-15,3 P20 GM103424-15S1

Department

College of Pharmacy

Document Type

Article

Publication Date

11-2018

Abstract

Factor XIa (FXIa) is a serine protease homodimer that belongs to the intrinsic coagulation pathway. FXIa primarily catalyzes factor IX activation to factor IXa, which subsequently activates factor X to factor Xa in the common coagulation pathway. Growing evidence suggests that FXIa plays an important role in thrombosis with a relatively limited contribution to hemostasis. Therefore, inhibitors targeting factor XI (FXI)/FXIa system have emerged as a paradigm-shifting strategy so as to develop a new generation of anticoagulants to effectively prevent and/or treat thromboembolic diseases without the life-threatening risk of internal bleeding. Several inhibitors of FXI/FXIa proteins have been discovered or designed over the last decade including polypeptides, active site peptidomimetic inhibitors, allosteric inhibitors, antibodies, and aptamers. Antisense oligonucleotides (ASOs), which ultimately reduce the hepatic biosynthesis of FXI, have also been introduced. A phase II study, which included patients undergoing elective primary unilateral total knee arthroplasty, revealed that a specific FXI ASO effectively protects patients against venous thrombosis with a relatively limited risk of bleeding. Initial findings have also demonstrated the potential of FXI/FXIa inhibitors in sepsis, listeriosis, and arterial hypertension. This review highlights various chemical, biochemical, and pharmacological aspects of FXI/FXIa inhibitors with the goal of advancing their development toward clinical use.

Comments

DOI: 10.1002/med.21503

PubMed ID: 29727017

  • Funding text #1

    Contract grant sponsor: Research Centers in Minority Institutions (RCMI) Program from the National Institute on Minority Health and Health Disparities of the National Institutes of Health

  • Funding text #2

    Contract grant number: 5G12MD007595

  • Funding text #3

    Contract grant sponsor: Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health

  • Funding text #4

    Contract grant numbers: 3 P20 GM103424-15S1 5, P20 GM103424-15

  • Funding text #5

    This publication was made possible by funding to RAAH from the Research Centers in Minority Institutions (RCMI) Program from the National Institute on Minority Health and Health Disparities of the National Institutes of Health (NIH) under grant number 5G12MD007595. This publication was also supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the NIH under grant numbers 5 P20 GM103424-15 and 3 P20 GM103424-15S1 to RAAH. The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

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