Skip to main content
SpringerLink
Log in

Development of Polar Organic Mode Chromatographic Method by Polysaccharide-Based Immobilized Chiral Selector and Validation for the Determination of the Enantiopurity of Novel Mineralocorticoid Receptor Antagonist Atropisomer–Esaxerenone

  • Original
  • Published:
Chromatographia Aims and scope Submit manuscript

Abstract

Esaxerenone is a new nonsteroidal mineralocorticoid receptor antagonist utilized to treat high blood pressure. Chemically, esaxerenone is a pyrrole derivative consisting of hindered rotation, which results in stereoisomers named atropisomers. Currently, no methods exist for the separation and quantification of these atropisomers. A new and accurate chiral liquid chromatographic technique was developed and validated to estimate the enantiomeric purity of esaxerenone. Polar organic chiral separation was carried out on an immobilized amylose-based chiral stationary phase (Chiralpak IG) with methanol:acetonitrile:diethylamine (9:1:0.1, v/v/v) mixture as a mobile phase. The total runtime was 15 min, and the resolution (Rs) between the atropisomers was more than 3.0. The detection and quantification thresholds for the R-atropisomer were found to be 0.03 and 0.1 µg mL−1, respectively, for a test concentration of esaxerenone (1000 µg mL−1). Over the range from the limit of quantification to 0.3 percent, the method's linearity for the R-atropisomer was excellent (R2 > 0.999). The R-atropisomer recovery varied from 95 to 102%, confirming the method’s good accuracy. For a 48-h research period, the chemical was shown to be stable.

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
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Whelton PK (1994) Epidemiology of hypertension. Lancet 344:101–106. https://doi.org/10.1016/s0140-6736(94)91285-8

    Article  CAS  PubMed  Google Scholar 

  2. MacMahon S, Peto R, Collins R et al (1990) Blood pressure, stroke, and coronary heart disease: Part 1, prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet 335:765–774. https://doi.org/10.1016/0140-6736(90)90878-9

    Article  CAS  PubMed  Google Scholar 

  3. Funder JW (2013) Mineralocorticoid receptor antagonists: emerging roles in cardiovascular medicine. Integr Blood Press Control 6:129–138. https://doi.org/10.2147/IBPC.S13783

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Young MJ, Funder JW (2002) Mineralocorticoid receptors and pathophysiological roles for aldosterone in the cardiovascular system. J Hypertens 20:1465–1468. https://doi.org/10.1097/00004872-200208000-00002

    Article  CAS  PubMed  Google Scholar 

  5. Jeunemaitre X, Chatellier G, Kreft-Jais C et al (1987) Efficacy and tolerance of spironolactone in essential hypertension. Am J Cardiol 60:820–825. https://doi.org/10.1016/0002-9149(87)91030-7

    Article  CAS  PubMed  Google Scholar 

  6. Croom KF, Perry CM (2005) Eplerenone: a review of its use in essential hypertension. Am J Cardiovasc Drugs 5:51–69. https://doi.org/10.2165/00129784-200505010-00007

    Article  CAS  PubMed  Google Scholar 

  7. Chapman N, Dobson J, Wilson S et al (2007) Effect of spironolactone on blood pressure in subjects with resistant hypertension. Hypertension 49:839–845. https://doi.org/10.1161/01.HYP.0000259805.18468.8c

    Article  CAS  PubMed  Google Scholar 

  8. Sternon J (1990) Spironolactone and altizide in systemic hypertension: ambulatory multicenter study. Am J Cardiol 65:K24–K27. https://doi.org/10.1016/0002-9149(90)91273-9

    Article  Google Scholar 

  9. White WB, Duprez D, St Hillaire R et al (2003) Effects of the selective aldosterone blocker eplerenone versus the calcium antagonist amlodipine in systolic hypertension. Hypertension 41:1021–1026. https://doi.org/10.1161/01.HYP.0000067463.13172.EA

    Article  CAS  PubMed  Google Scholar 

  10. The RALES Investigators (1996) Effectiveness of spironolactone added to an angiotensin-converting enzyme inhibitor and a loop diuretic for severe chronic congestive heart failure (The Randomized Aldactone Evaluation Study [RALES]). Am J Cardiol 78:902–907. https://doi.org/10.1016/S0002-9149(96)00465-1

    Article  Google Scholar 

  11. Pitt B, Remme W, Zannad F et al (2003) Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 348:1309–1321. https://doi.org/10.1056/NEJMoa030207

    Article  CAS  PubMed  Google Scholar 

  12. Zannad F, McMurray JJV, Krum H et al (2011) Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 364:11–21. https://doi.org/10.1056/NEJMoa1009492

    Article  CAS  PubMed  Google Scholar 

  13. Sica DA (2005) Pharmacokinetics and pharmacodynamics of mineralocorticoid blocking agents and their effects on potassium homeostasis. Heart Fail Rev 10:23–29. https://doi.org/10.1007/s10741-005-2345-1

    Article  CAS  PubMed  Google Scholar 

  14. Sica DA (2002) Eplerenone: a new aldosterone receptor antagonist—are the fda’s restrictions appropriate. J Clin Hypertens 4:441–445. https://doi.org/10.1111/j.1524-6175.2002.01510.x

    Article  CAS  Google Scholar 

  15. Takahashi S, Hiramatsu M, Hotta S et al (2016) Safety and antihypertensive effect of Selara® (Eplerenone): results from a postmarketing surveillance in Japan. Int J Hypertens 2016:e5091951. https://doi.org/10.1155/2016/5091951

    Article  CAS  Google Scholar 

  16. Daiichi Sankyo (2019) Daiichi Sankyo announces approval of MINNEBRO(TM) tablets for the treatment of hypertension in Japan - Press Releases - Media - Daiichi Sankyo. Accessed 11 Oct 2021

  17. Ito S, Itoh H, Rakugi H et al (2020) Double-blind randomized phase 3 study comparing esaxerenone (CS-3150) and eplerenone in patients with essential hypertension (ESAX-HTN study). Hypertension 75:51–58. https://doi.org/10.1161/HYPERTENSIONAHA.119.13569

    Article  CAS  PubMed  Google Scholar 

  18. Arai K, Tsuruoka H, Homma T (2015) CS-3150, a novel nonsteroidal mineralocorticoid receptor antagonist, prevents hypertension and cardiorenal injury in Dahl salt-sensitive hypertensive rats. Eur J Pharmacol 769:266–273. https://doi.org/10.1016/j.ejphar.2015.11.028

    Article  CAS  PubMed  Google Scholar 

  19. Arai K, Morikawa Y, Ubukata N et al (2016) CS-3150, a novel nonsteroidal mineralocorticoid receptor antagonist, shows preventive and therapeutic effects on renal injury in deoxycorticosterone acetate/salt-induced hypertensive rats. J Pharmacol Exp Ther 358:548–557. https://doi.org/10.1124/jpet.116.234765

    Article  CAS  PubMed  Google Scholar 

  20. Kato M, Furuie H, Shimizu T et al (2018) Single- and multiple-dose escalation study to assess pharmacokinetics, pharmacodynamics, and safety of oral esaxerenone in healthy Japanese subjects. Br J Clin Pharmacol 84:1821–1829. https://doi.org/10.1111/bcp.13616

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Satoh F, Ito S, Itoh H et al (2021) Efficacy and safety of esaxerenone (CS-3150), a newly available nonsteroidal mineralocorticoid receptor blocker, in hypertensive patients with primary aldosteronism. Hypertens Res 44:464–472. https://doi.org/10.1038/s41440-020-00570-5

    Article  CAS  PubMed  Google Scholar 

  22. Yang P, Shen W, Chen X et al (2019) Comparative efficacy and safety of mineralocorticoid receptor antagonists in heart failure: a network meta-analysis of randomized controlled trials. Heart Fail Rev 24:637–646. https://doi.org/10.1007/s10741-019-09790-5

    Article  CAS  PubMed  Google Scholar 

  23. Umemura S (2019) The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2019). Hypertens Res 42:1235–1481. https://doi.org/10.1038/s41440-019-0284-9

    Article  PubMed  Google Scholar 

  24. PubChem (2021) Esaxerenone, CID: 25052023. https://pubchem.ncbi.nlm.nih.gov/compound/25052023. Accessed 25 Oct 2021

  25. Drugbank (2021) Esaxerenone, Accession number:DB15207. https://go.drugbank.com/drugs/DB15207. Accessed 26 Oct 2021

  26. Yamada M, Takei M, Suzuki E et al (2017) Pharmacokinetics, distribution, and disposition of esaxerenone, a novel, highly potent and selective nonsteroidal mineralocorticoid receptor antagonist, in rats and monkeys. Xenobiotica 47:1090–1103. https://doi.org/10.1080/00498254.2016.1263766

    Article  CAS  PubMed  Google Scholar 

  27. Wipf P, Skoda EM, Mann A (2015) Conformational restriction and steric hindrance in medicinal chemistry. The practice of medicinal chemistry. Elsevier, Amsterdam, pp 279–299

    Chapter  Google Scholar 

  28. Zask A, Murphy J, Ellestad GA (2013) Biological stereoselectivity of atropisomeric natural products and drugs: biological-stereoselectivity of atropisomeric natural products and drugs. Chirality 25:265–274. https://doi.org/10.1002/chir.22145

    Article  CAS  PubMed  Google Scholar 

  29. LaPlante SR, Fader LD, Fandrick KR et al (2011) Assessing Atropisomer Axial Chirality In Drug Discovery And Development. J Med Chem 54:7005–7022. https://doi.org/10.1021/jm200584g

    Article  CAS  PubMed  Google Scholar 

  30. LaPlante SR, Edwards PJ, Fader LD et al (2011) Revealing atropisomer axial chirality in drug discovery. ChemMedChem 6:505–513. https://doi.org/10.1002/cmdc.201000485

    Article  CAS  PubMed  Google Scholar 

  31. Patel MA, Riley F, Ashraf-Khorassani M, Taylor LT (2012) Supercritical fluid chromatographic resolution of water soluble isomeric carboxyl/amine terminated peptides facilitated via mobile phase water and ion pair formation. J Chromatogr A 1233:85–90. https://doi.org/10.1016/j.chroma.2012.02.024

    Article  CAS  PubMed  Google Scholar 

  32. Yaku K, Aoe K, Nishimura N et al (1997) Chiral resolution of four optical isomers of diltiazem hydrochloride on Chiralcel columns by packed-column supercritical fluid chromatography. J Chromatogr A 785:185–193. https://doi.org/10.1016/S0021-9673(97)00623-7

    Article  CAS  Google Scholar 

  33. Loukotková L, Tesařová E, Bosáková Z et al (2010) Comparison of HPLC enantioseparation of substituted binaphthyls on CD-, polysaccharide- and synthetic polymer-based chiral stationary phases: liquid Chromatography. J Sep Science 33:1244–1254. https://doi.org/10.1002/jssc.200900796

    Article  CAS  Google Scholar 

  34. Schurig V (2001) Separation of enantiomers by gas chromatography. J Chromatogr A 906:275–299. https://doi.org/10.1016/S0021-9673(00)00505-7

    Article  CAS  PubMed  Google Scholar 

  35. Zerbinati O, Trotta F (2003) pH-dependent cyclodextrin capillary electrophoresis resolution of atropisomers. Electrophoresis 24:2456–2461. https://doi.org/10.1002/elps.200305518

    Article  CAS  PubMed  Google Scholar 

  36. Okamoto Y, Yashima E (1998) Polysaccharide derivatives for chromatographic separation of enantiomers. Angew Chem Int Ed 37:1020–1043. https://doi.org/10.1002/(SICI)1521-3773(19980504)37:8%3c1020::AID-ANIE1020%3e3.0.CO;2-5

    Article  Google Scholar 

Download references

Acknowledgements

The authors wish to acknowledge the team of the National Institute of Pharmaceutical Education and Research, Guwahati, and Daicel Chiral Technologies, India, for supporting this work and for their cooperation in performing this work.

Funding

The work was supported by the Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govt. of India.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, Assam, 781101, India

    P. Radhakrishnanand, V. V. S. Prasanna Kumari Rayala, Kashyap Trivedi & Upadhyayula Suryanarayana Murty

  2. Daicel Chiral Technologies-India (P) Limited, Hyderabad, Telangana, 500101, India

    Gunnam Srinivasu

Authors
  1. P. Radhakrishnanand
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. V. V. S. Prasanna Kumari Rayala
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kashyap Trivedi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Upadhyayula Suryanarayana Murty
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gunnam Srinivasu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the study conception and design. Method development and validation were performed by VVSPKR and GS. The first draft of the manuscript was written by VVSPKR, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to P. Radhakrishnanand.

Ethics declarations

Conflict of Interest

The authors have no relevant financial or non-financial interests to disclose. The authors declare that there are no conflicts of interest.

Ethical Approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Radhakrishnanand, P., Rayala, V.V.S.P.K., Trivedi, K. et al. Development of Polar Organic Mode Chromatographic Method by Polysaccharide-Based Immobilized Chiral Selector and Validation for the Determination of the Enantiopurity of Novel Mineralocorticoid Receptor Antagonist Atropisomer–Esaxerenone. Chromatographia 85, 553–562 (2022). https://doi.org/10.1007/s10337-022-04164-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10337-022-04164-w

Keywords

Search

Navigation