Skip to main content

Advertisement

SpringerLink
Log in

Structure–function relationships of factor Xa inhibitors: implications for the practicing clinician

  • Published:
Journal of Thrombosis and Thrombolysis Aims and scope Submit manuscript

Abstract

The recent development and approval of novel oral anticoagulants represents a significant success in the intelligent design of target-specific therapeutics. However, while these agents obviate many of the shortcomings of their predecessor (warfarin), they present novel challenges in pharmacologic management as well. Each was designed to have high oral bioavailability and high affinity for its target molecule, conveying significant anticoagulant effects. Yet, such unique drug–ligand binding, coupled with unfamiliar drug interactions and renal-based clearance, represent challenges to clinical management. The current review describes the development and pharmacokinetic properties of these agents, in the context of their clinical utility and pitfalls.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L (2009) Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 361(12):1139–1151. doi:10.1056/NEJMoa0905561

    Article  CAS  PubMed  Google Scholar 

  2. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, Califf RM (2011) Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 365(10):883–891. doi:10.1056/NEJMoa1009638

    Article  CAS  PubMed  Google Scholar 

  3. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FW, Zhu J, Wallentin L (2011) Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 365(11):981–992. doi:10.1056/NEJMoa1107039

    Article  CAS  PubMed  Google Scholar 

  4. Davie EW, Fujikawa K, Kisiel W (1991) The coagulation cascade: initiation, maintenance, and regulation. Biochemistry 30(43):10363–10370

    Article  CAS  PubMed  Google Scholar 

  5. Perzborn E, Roehrig S, Straub A, Kubitza D, Misselwitz F (2011) The discovery and development of rivaroxaban, an oral, direct factor Xa inhibitor. Nat Rev Drug Discov 10(1):61–75. doi:10.1038/nrd3185

    Article  CAS  PubMed  Google Scholar 

  6. Weitz JI (2011) Factor Xa and thrombin as targets for new oral anticoagulants. Thromb Res 127(Suppl 2):S5–S12. doi:10.1016/s0049-3848(10)70147-x

    Article  CAS  PubMed  Google Scholar 

  7. Hauel NH, Nar H, Priepke H, Ries U, Stassen JM, Wienen W (2002) Structure-based design of novel potent nonpeptide thrombin inhibitors. J Med Chem 45(9):1757–1766

    Article  CAS  PubMed  Google Scholar 

  8. Rawlings ND, Barrett AJ (1993) Evolutionary families of peptidases. Biochem J 290(Pt 1):205–218

    CAS  PubMed  Google Scholar 

  9. Krishnaswamy S (2005) Exosite-driven substrate specificity and function in coagulation. J Thromb Haemost 3(1):54–67. doi:10.1111/j.1538-7836.2004.01021.x

    Article  CAS  PubMed  Google Scholar 

  10. Perzborn E, Strassburger J, Wilmen A, Pohlmann J, Roehrig S, Schlemmer KH, Straub A (2005) In vitro and in vivo studies of the novel antithrombotic agent BAY 59-7939—an oral, direct factor Xa inhibitor. J Thromb Haemost 3(3):514–521. doi:10.1111/j.1538-7836.2005.01166.x

    Article  CAS  PubMed  Google Scholar 

  11. Wong PC, Pinto DJ, Zhang D (2011) Preclinical discovery of apixaban, a direct and orally bioavailable factor Xa inhibitor. J Thromb Thrombolysis 31(4):478–492. doi:10.1007/s11239-011-0551-3

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Wilkens M, Krishnaswamy S (2002) The contribution of factor Xa to exosite-dependent substrate recognition by prothrombinase. J Biol Chem 277(11):9366–9374. doi:10.1074/jbc.M110848200

    Article  CAS  PubMed  Google Scholar 

  13. Corte JR, Fang T, Pinto DJ, Han W, Hu Z, Jiang XJ, Li YL, Gauuan JF, Hadden M, Orton D, Rendina AR, Luettgen JM, Wong PC, He K, Morin PE, Chang CH, Cheney DL, Knabb RM, Wexler RR, Lam PY (2008) Structure–activity relationships of anthranilamide-based factor Xa inhibitors containing piperidinone and pyridinone P4 moieties. Bioorg Med Chem Lett 18(9):2845–2849. doi:10.1016/j.bmcl.2008.03.092

    Article  CAS  PubMed  Google Scholar 

  14. Furugohri T, Shiozaki Y, Muramatsu S, Honda Y, Matsumoto C, Isobe K, Sugiyama N (2005) Different antithrombotic properties of factor Xa inhibitor and thrombin inhibitor in rat thrombosis models. Eur J Pharmacol 514(1):35–42. doi:10.1016/j.ejphar.2005.03.009

    Article  CAS  PubMed  Google Scholar 

  15. Eriksson BI, Quinlan DJ, Weitz JI (2009) Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor Xa inhibitors in development. Clin Pharmacokinet 48(1):1–22

    CAS  PubMed  Google Scholar 

  16. Mega JL, Braunwald E, Wiviott SD, Bassand JP, Bhatt DL, Bode C, Burton P, Cohen M, Cook-Bruns N, Fox KA, Goto S, Murphy SA, Plotnikov AN, Schneider D, Sun X, Verheugt FW, Gibson CM (2012) Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 366(1):9–19. doi:10.1056/NEJMoa1112277

    Article  CAS  PubMed  Google Scholar 

  17. Wong PC, Crain EJ, Xin B, Wexler RR, Lam PY, Pinto DJ, Luettgen JM, Knabb RM (2008) Apixaban, an oral, direct and highly selective factor Xa inhibitor: in vitro, antithrombotic and antihemostatic studies. J Thromb Haemost 6(5):820–829. doi:10.1111/j.1538-7836.2008.02939.x

    Article  CAS  PubMed  Google Scholar 

  18. Pinto DJ, Orwat MJ, Koch S, Rossi KA, Alexander RS, Smallwood A, Wong PC, Rendina AR, Luettgen JM, Knabb RM, He K, Xin B, Wexler RR, Lam PY (2007) Discovery of 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H -pyrazolo[3,4-c]pyridine-3-carboxamide (apixaban, BMS-562247), a highly potent, selective, efficacious, and orally bioavailable inhibitor of blood coagulation factor Xa. J Med Chem 50(22):5339–5356. doi:10.1021/jm070245n

    Article  CAS  PubMed  Google Scholar 

  19. Alexander JH, Lopes RD, James S, Kilaru R, He Y, Mohan P, Bhatt DL, Goodman S, Verheugt FW, Flather M, Huber K, Liaw D, Husted SE, Lopez-Sendon J, De Caterina R, Jansky P, Darius H, Vinereanu D, Cornel JH, Cools F, Atar D, Leiva-Pons JL, Keltai M, Ogawa H, Pais P, Parkhomenko A, Ruzyllo W, Diaz R, White H, Ruda M, Geraldes M, Lawrence J, Harrington RA, Wallentin L (2011) Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med 365(8):699–708. doi:10.1056/NEJMoa1105819

    Article  CAS  PubMed  Google Scholar 

  20. Connolly SJ, Eikelboom J, Joyner C, Diener HC, Hart R, Golitsyn S, Flaker G, Avezum A, Hohnloser SH, Diaz R, Talajic M, Zhu J, Pais P, Budaj A, Parkhomenko A, Jansky P, Commerford P, Tan RS, Sim KH, Lewis BS, Van Mieghem W, Lip GY, Kim JH, Lanas-Zanetti F, Gonzalez-Hermosillo A, Dans AL, Munawar M, O’Donnell M, Lawrence J, Lewis G, Afzal R, Yusuf S (2011) Apixaban in patients with atrial fibrillation. N Engl J Med 364(9):806–817. doi:10.1056/NEJMoa1007432

    Article  CAS  PubMed  Google Scholar 

  21. Ruff CT, Giugliano RP, Antman EM, Crugnale SE, Bocanegra T, Mercuri M, Hanyok J, Patel I, Shi M, Salazar D, McCabe CH, Braunwald E (2010) Evaluation of the novel factor Xa inhibitor edoxaban compared with warfarin in patients with atrial fibrillation: design and rationale for the Effective aNticoaGulation with factor xA next GEneration in Atrial Fibrillation-Thrombolysis In Myocardial Infarction study 48 (ENGAGE AF-TIMI 48). Am Heart J 160(4):635–641. doi:10.1016/j.ahj.2010.06.042

    Article  CAS  PubMed  Google Scholar 

  22. Bathala MS, Masumoto H, Oguma T, He L, Lowrie C, Mendell J (2012) Pharmacokinetics, biotransformation, and mass balance of edoxaban, a selective, direct factor Xa inhibitor, in humans. Drug Metab Dispos 40(12):2250–2255. doi:10.1124/dmd.112.046888

    Article  CAS  PubMed  Google Scholar 

  23. Zhang P, Huang W, Wang L, Bao L, Jia ZJ, Bauer SM, Goldman EA, Probst GD, Song Y, Su T, Fan J, Wu Y, Li W, Woolfrey J, Sinha U, Wong PW, Edwards ST, Arfsten AE, Clizbe LA, Kanter J, Pandey A, Park G, Hutchaleelaha A, Lambing JL, Hollenbach SJ, Scarborough RM, Zhu BY (2009) Discovery of betrixaban (PRT054021), N-(5-chloropyridin-2-yl)-2-(4-(N,N-dimethylcarbamimidoyl)benzamido)-5-methoxybenz amide, a highly potent, selective, and orally efficacious factor Xa inhibitor. Bioorg Med Chem Lett 19(8):2179–2185. doi:10.1016/j.bmcl.2009.02.111

    Article  CAS  PubMed  Google Scholar 

  24. Connolly SJ, Eikelboom J, Dorian P, Hohnloser SH, Gretler DD, Sinha U, Ezekowitz MD (2013) Betrixaban compared with warfarin in patients with atrial fibrillation: results of a phase 2, randomized, dose-ranging study (Explore-Xa). Eur Heart J 34(20):1498–1505. doi:10.1093/eurheartj/eht039

    Article  CAS  PubMed  Google Scholar 

  25. Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M (2011) Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 124(14):1573–1579. doi:10.1161/circulationaha.111.029017

    Article  CAS  PubMed  Google Scholar 

  26. Lu G, DeGuzman FR, Hollenbach SJ, Karbarz MJ, Abe K, Lee G, Luan P, Hutchaleelaha A, Inagaki M, Conley PB, Phillips DR, Sinha U (2013) A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med 19(4):446–451. doi:10.1038/nm.3102

    Article  CAS  PubMed  Google Scholar 

  27. Wang L, He K, Maxwell B, Grossman SJ, Tremaine LM, Humphreys WG, Zhang D (2011) Tissue distribution and elimination of [14C]apixaban in rats. Drug Metab Dispos 39(2):256–264. doi:10.1124/dmd.110.036442

    Article  CAS  PubMed  Google Scholar 

  28. Gnoth MJ, Buetehorn U, Muenster U, Schwarz T, Sandmann S (2011) In vitro and in vivo P-glycoprotein transport characteristics of rivaroxaban. J Pharmacol Exp Ther 338(1):372–380. doi:10.1124/jpet.111.180240

    Article  CAS  PubMed  Google Scholar 

  29. Weinz C, Buetehorn U, Daehler HP, Kohlsdorfer C, Pleiss U, Sandmann S, Schlemmer KH, Schwarz T, Steinke W (2005) Pharmacokinetics of BAY 59-7939—an oral, direct Factor Xa inhibitor—in rats and dogs. Xenobiotica 35(9):891–910. doi:10.1080/00498250500250493

    Article  CAS  PubMed  Google Scholar 

  30. Hart RG, Diener HC, Yang S, Connolly SJ, Wallentin L, Reilly PA, Ezekowitz MD, Yusuf S (2012) Intracranial hemorrhage in atrial fibrillation patients during anticoagulation with warfarin or dabigatran: the RE-LY trial. Stroke 43(6):1511–1517. doi:10.1161/strokeaha.112.650614

    Article  CAS  PubMed  Google Scholar 

  31. Monroe DM, Hoffman M, Oliver JA, Roberts HR (1997) Platelet activity of high-dose factor VIIa is independent of tissue factor. Br J Haematol 99(3):542–547

    Article  CAS  PubMed  Google Scholar 

  32. Siegal DM, Cuker A (2013) Reversal of novel oral anticoagulants in patients with major bleeding. J Thromb Thrombolysis. doi:10.1007/s11239-013-0885-0

    PubMed  Google Scholar 

  33. Asmis LM, Alberio L, Angelillo-Scherrer A, Korte W, Mendez A, Reber G, Seifert B, Stricker H, Tsakiris DA, Wuillemin WA (2012) Rivaroxaban: quantification by anti-FXa assay and influence on coagulation tests: a study in 9 Swiss laboratories. Thromb Res 129(4):492–498. doi:10.1016/j.thromres.2011.06.031

    Article  CAS  PubMed  Google Scholar 

  34. Becker RC, Yang H, Barrett Y, Mohan P, Wang J, Wallentin L, Alexander JH (2011) Chromogenic laboratory assays to measure the factor Xa-inhibiting properties of apixaban—an oral, direct and selective factor Xa inhibitor. J Thromb Thrombolysis 32(2):183–187. doi:10.1007/s11239-011-0591-8

    Article  PubMed  Google Scholar 

  35. Roehrig S, Straub A, Pohlmann J, Lampe T, Pernerstorfer J, Schlemmer KH, Reinemer P, Perzborn E (2005) Discovery of the novel antithrombotic agent 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide (BAY 59-7939): an oral, direct factor Xa inhibitor. J Med Chem 48(19):5900–5908. doi:10.1021/jm050101d

    Article  CAS  PubMed  Google Scholar 

  36. Furugohri T, Isobe K, Honda Y, Kamisato-Matsumoto C, Sugiyama N, Nagahara T, Morishima Y, Shibano T (2008) DU-176b, a potent and orally active factor Xa inhibitor: in vitro and in vivo pharmacological profiles. J Thromb Haemost 6(9):1542–1549. doi:10.1111/j.1538-7836.2008.03064.x

    CAS  PubMed  Google Scholar 

  37. Ogata K, Mendell-Harary J, Tachibana M, Masumoto H, Oguma T, Kojima M, Kunitada S (2010) Clinical safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel factor Xa inhibitor edoxaban in healthy volunteers. J Clin Pharmacol 50(7):743–753. doi:10.1177/0091270009351883

    Article  CAS  PubMed  Google Scholar 

  38. Turpie AG (2008) New oral anticoagulants in atrial fibrillation. Eur Heart J 29(2):155–165. doi:10.1093/eurheartj/ehm575

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Dr. Steinberg was funded by NIH T-32 training Grant #5 T32 HL 7101-37. The authors wish to acknowledge Ms. Seanna Horar for her graphic design input.

Author information

Authors and Affiliations

  1. Duke University Medical Center, PO Box 17969, Durham, NC, 27715, USA

    Benjamin A. Steinberg & Richard C. Becker

  2. Duke Clinical Research Institute, Durham, NC, USA

    Benjamin A. Steinberg & Richard C. Becker

Authors
  1. Benjamin A. Steinberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Richard C. Becker
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Benjamin A. Steinberg.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Steinberg, B.A., Becker, R.C. Structure–function relationships of factor Xa inhibitors: implications for the practicing clinician. J Thromb Thrombolysis 37, 234–241 (2014). https://doi.org/10.1007/s11239-013-0991-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11239-013-0991-z

Keywords

Search

Navigation