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Update on the Chemistry of Jardiance (Empagliflozin)

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Review Article | DOI: https://doi.org/10.31579/2688-7517/199

Update on the Chemistry of Jardiance (Empagliflozin)

  • Ravi Varala 1*
  • Narsimhaswamy Dubasi 2

1Scrips Pharma, Mallapur, Hyderabad-500 076, Telangana, India & Research Fellow, INTI International University, Malaysia

2Independent Researcher,12001, Belcher Rd S, Apt. No. 226, Largo, Florida33773, USA

*Corresponding Author: Ravi Varala, B N University, Department of Pharmacology, Udaipur, Rajasthan, India.

Citation: Ravi Varala, Narsimhaswamy Dubasi, (2024), Update on the Chemistry of Jardiance (Empagliflozin), J. Pharmaceutics and Pharmacology Research, 7(7); DOI:10.31579/2688-7517/199

Copyright: © 2024, Ravi Varala. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Received: 07 June 2024 | Accepted: 17 June 2024 | Published: 10 July 2024

Keywords: type 2 diabetes (t2dm); sglt-2 inhibitors (gliflozins); jardiance (empagliflozin)

Abstract

In this perspective, we put forth glimpses of type 2 diabetes (T2DM), SGLT-2 inhibitors (gliflozins), jardiance (Empagliflozin) and synthetic approaches towards empagliflozin and literature is covered up to date.

Introduction

Diabetes is a long-term metabolic illness marked by high blood glucose (blood sugar) levels. Serious damage to the heart, blood vessels, eyes, kidneys, and nerves can result from diabetes over time. The most prevalent kind, type 2 diabetes, usually affects adults and is brought on by insufficient or resistant insulin production in the body. Type 2 diabetes (T2DM) has been much more common over the last three decades in all nations, regardless of economic status.1 Diabetes type 1 is a chronic illness in which the pancreas generates little or no insulin on its own. It was formerly referred to as juvenile diabetes or insulin-dependent diabetes. Having access to reasonably priced therapy, such as insulin, is essential for the survival of those with diabetes. By 2025, there is a goal set globally to stop the rise in diabetes and obesity. 

Approximately 422 million individuals globally suffer from diabetes, with the majority residing in low- and middle-income nations. The disease is directly responsible for 1.5 million fatalities annually. Over the past few decades, there has been a steady rise in both the number of cases and the incidence of diabetes. 

The World Health Organisation (WHO) introduced the worldwide Diabetes Compact in April 2021. This worldwide initiative aims to support low- and middle-income nations while promoting sustained gains in diabetes prevention and care.2 The World Health Organisation introduced the Global Diabetes Compact in response to the growing global burden of diabetes. The launch takes place on the 100th anniversary of insulin's discovery. The goal of the WHO Global Diabetes Compact is to lower the risk of diabetes and guarantee that everyone with the disease has access to fair, thorough, reasonably priced, and high-quality care. The work that is being done as part of the Compact will also help to prevent type 2 diabetes from being brought on by obesity, poor diet, and inactivity. The World Health Assembly passed a resolution in May 2021 aimed at enhancing diabetes prevention and control. The World Health Assembly approved five worldwide goals for diabetes treatment and coverage in May 2022, with an objective of achieving them by 2030.[3] 
 Certain individuals diagnosed with type 2 diabetes may require medication to assist in controlling their blood sugar levels. Injections of insulin or other medications are examples of these. Sulfonylureas, metformin, and inhibitors of the sodium-glucose co-transporter type 2 (SGLT-2) are a few examples.

SGLT-2 inhibitors (Gliflozins)

Sodium-glucose co-transporter-2 (SGLT-2) inhibitors are antihyperglycemic agents acting on the SGLT-2 proteins expressed in the proximal convoluted tubules. These medications work by stopping the tubular lumen's filtered glucose from being reabsorbed. [4-6] A new class of glucose-lowering medicines known as gliflozins is defined by derivatives of β-D-glucoside that have an aryl or heteroaryl aglycone linked to the anomeric carbon (Figure 1). [28].A methylene bridge joins the aryl and heteroaryl groups in the β-C-glucoside aglycones. 


 

Figure 1. SGLT-2 inhibitors (Gliflozins)


 

In the US, there are presently three SGLT2 inhibitors on the market. The US Food and Drug Administration (FDA) approved dapagliflozin in January 2014, empagliflozin in August 2014, and canagliflozin in March 2013 (FDA news release 2013).7-9 While canagliflozin exhibits dual blockage of SGLT1 and SGLT2, dapagliflozin and empagliflozin are highly selective for SGLT2. All of these drugs are strong competitive inhibitors of the SGLT2 protein. Empagliflozin, out of the three SGLT2 inhibitors that are currently on the market, has the highest selectivity for SGLT2 (2500-fold) when compared to SGLT1. [10-13].

At least two of the other three medications in this class-ipragliflozin, luseogliflozin, and tofogliflozin-are presently being studied, and ertugliflozin and remogliflozin are the other two that are marketed in Japan. Steglatro is the brand name under which ertugliflozin was approved in the United States in December 2017. Clinical trials on remogliflozin etabonate were terminated. Phase II trials saw the discontinuation of sergliflozin etabonate. Sotagliflozin, a combination SGLT1 and 2 inhibitors, was also undergoing clinical studies. Under the brand name Zynquista, sotagliflozin is a dual SGLT1/SGLT2 inhibitor undergoing phase III trials through March 2019. If authoriZed, sotagliflozin, which was developed by Lexicon Pharmaceuticals, would be the first oral medication used in conjunction with insulin to treat type 1 diabetes mellitus. According to a press statement from Sanofi and Lexicon, the FDA completed its response letter to a new drug application in March 2019 about oral sotagliflozin, a first-in-class dual SGLT1 and SGLT2 inhibitor for adults with type 1 diabetes. In this viewpoint, we provide a quick overview of the latest developments in the synthesis and uses of empagliflozin, with a particular emphasis.

Jardiance (Empagliflozin)

Empagliflozin, also marketed as Jardiance (BI 10773, Figure 2), is a strong, competitive, and specific inhibitor of the sodium glucose transporter SGLT2,14-22 which mediates most of the kidney's total glucose reabsorption as well as glucose reabsorption in the early proximal tubule. As a result, therapy with empagliflozin enhanced the excretion of glucose in the urine. An FDA-approved pill called Jardiance is used to treat persons with heart failure or cardiovascular disease who also have type 2 diabetes (T2DM) lower their risk of cardiovascular complications. Jardiance helps the kidney increase the amount of glucose that passes into the urine, which reduces blood glucose levels (HbA1c). Jardiance is not advised for those with type 1 diabetes mellitus because it may raise their chance of developing diabetic ketoacidosis, which is characterised by elevated blood or urine ketones.


 

 

Figure 2. Jardiance


 

In 2014, both the European Union and the United States approved the medicinal use of empagliflozin. It is included in the List of Essential Medicines by the World Health Organisation. With around 8 million prescriptions, it ranked as the 85th most often prescribed drug in the US in 2021. The US Food and Drug Administration (FDA) has approved it for use as a generic drug. As of May 2013, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) had received applications for marketing approval from Boehringer and Lilly. The medication received approval in the US in August 2014 after receiving approval in the EU in May of the same year. Four postmarketing studies were mandated by the FDA: two studies involving children, a toxicity study with animals connected to the paediatric trials, and a cardiovascular outcomes trial. There are currently four different formulations available on the market: Synjardy (empagliflozin and metformin, film-coated tablets: 5 mg or 12.5 mg/1000 mg, and 5 mg/850 mg), Glyxambi (empagliflozin and linagliptin, 10/5 mg or 25/5 mg tablets), and Jardiance (empagliflozin, 10 mg/25 mg tablets). 
Very recently, absolute configuration of empagliflozin was re-confirmed by Sun et al.23 A small number of study groups also conducted qualitative analyses of the empagliflozin impurity profiles. [24-26] An alginate-chitosan nanocarrier technology for efficient empagliflozin delivery was described by Mahmoodi and Ramazanzadeh.27 There have been numerous patents and articles since its discovery and FDA approval. The short description and synthesis of empagliflozin can be found below.[28-29]

Synthetic approaches towards Empagliflozin

  1. Martin et al. (2006)30

An early discovery patent (WO2006117359, 2006) describing the synthesis of empagliflozin is discussed in Scheme 1 The synthesis involved a total of eight steps with an overall yield of 8% and commences from commercially available 2-chloro-5-bromobenzoic acid.


 

Scheme 1. Martin’s synthetic approach


 

  1. Wang et al. (2014) [31]

An efficient production synthesis of the SGLT-2 inhibitor Empagliflozin from acid 2-chloro-5-iodobenzoic acid is described (Scheme 2). The key tactical stage involves I/Mg exchange of aryl iodide 2 followed by addition to glucono lactone in THF. Subsequent in situ treatment of the 

 

resulting lactol with HCl in MeOH produces β-anomeric methyl glycopyranoside which is, without isolation, directly reduced with Et3SiH mediated by AlCl3 as a Lewis acid in CH2Cl2/MeCN to afford empagliflozin in 50% overall yield. The process was implemented for production on a metric ton scale for commercial launch.


 

Scheme 2. Wang’s synthetic approach


 

  1. Latli et al. (2014) [32]

Authors reported the synthesis of carbon-13 and carbon-14 labeled empagliflozin. Carbon-13 labeled empagliflozin was prepared in five steps and in 34% overall chemical yield starting from the commercially available α-D-glucose-[13C6] (Scheme 3). For the radiosynthesis, the carbon-14 atom was introduced in three different positions of the molecule. In the first synthesis, Carbon-14 D-(+)-gluconic acid δ-lactone was used to prepare specifically labeled empagliflozin in carbon-1 of the sugar moiety in four steps and in 19% overall radiochemical yield. Carbon-14 labeled empagliflozin with the radioactive atom in the benzylic position was obtained in eight steps and in 7% overall radiochemical yield. In the last synthesis carbon-14 uniformly labeled phenol was used to give [14C] empagliflozin in eight steps and in 18% overall radiochemical yield. In all these radiosyntheses, the specific activities of the final compounds were higher than 53 mCi/mmol, and the radiochemical purities were above 98.5%.


 

Scheme 3. Latli’s synthetic approach


 

Furthermore, numerous studies in the literature have focused on the synthesis of radiolabelled empagliflozin. Hrapchak’s team have detailed the synthesis of 13C- and 14Clabelled empagliflozin, commencing from a-D-glucose-[13C6] (Scheme 3). This five-step process resulted in the desired 13C-labelled empagliflozin with an overall yield of 34% starting from a-D-glucose-[13C6] intermediate, which was itself prepared from the corresponding carboxylic acid.

  1. Kaushik et al. (2015) [33]

In 2015, Kaushik and co-workers patented an improved process for synthesizing empagliflozin starting from 5-bromo-chlorobenzaldehyde (Scheme 4).


 

Scheme 4. Kaushik’s synthetic approach


 

  1. Sethi et al. (2018) [34]

An efficient synthetic process consisting usage of two novel intermediates namely [(5-Bromo-2-chlorophenyl) {4-[(3S)-tetrahydrofuran-3-yloxy] phenyl} methyl and 1-C-[4-chloro-3-(methoxy{4-[(3S)-tetrahydrofuran-

3-yloxy] phenyl} methyl) phenyl]-α-Dglucopyranose has been developed to produce compound empagliflozin. This manuscript describes the comprehensive experimentation of this innovative and scale-up with ease synthetic route. 


 

Scheme 5. Sethi’s synthetic approach


 

  1. Walczak et al. (2018) [35]

A stereospecific cross-coupling reaction of anomeric nucleophiles with diaryliodonium triflates resulting in the synthesis of aryl C-glycosides was reported (Scheme 6). This process capitalizes on a stereoretentive reaction of configurationally stable C1 stannanes and is promoted by a palladium catalyst in the presence of a bulky phosphine ligand that suppresses the undesired β-elimination. The utility of this reaction has been demonstrated in the preparation of a series of C-glycosides derived from common saccharides resulting in exclusive transfer of anomeric configuration from the anomeric nucleophile to the product, and in the synthesis of empagliflozin, a commercial antidiabetic drug.


 

Scheme 6. Walczak’s synthetic approach


 

  1. Reddy et al. (2019) [36]

Chiral 4,4-dimethyl tetrahydrofuran (THF) derivatives were synthesized from commercially available D-(-)/ L-(+) pantolactones, which can serve as chiral building blocks in medicinal chemistry. In addition, two of the synthesized building blocks were utilized for the synthesis of new amprenavir (HIV protease inhibitor) and empagliflozin (anti-diabetic) analogs Scheme 7. The synthesized analogs may have beneficial effects in terms of pharmacokinetics and modulation of bioactivity.


 

Scheme 7. Reddy’s synthetic approach


 

(g) Kitamura et al. (2023) [37]

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are clinically available to control blood glucose levels in diabetic patients via an insulin-independent mechanism. It was found that some carbasugar analogs of known SGLT2 inhibitors exert a high inhibiting ability toward SGLT2 and have a prolonged blood glucose lowering effect. In this study, authors designed new candidates of carbasugar SGLT2 inhibitor that can be synthesized using copper-catalyzed azide–alkyne cycloaddition (CuAAC) into an aromatic ring (Scheme 8), which is a part of the pharmacophore at the final stage in the synthetic protocol for the easier discovery of superior SGLT2 inhibitors. Based on the results of molecular docking studies, some selected compounds have been synthesized. Evaluation of these compounds using a cell-based assay revealed that the majority of these compounds had SGLT2 inhibitory activity in a dose-dependent manner. 


Conclusion

The purpose of this perspective is to provide brief glimpse about type 2 Diabetes mellitus (T2DM), SGLT-2 inhibitors (gliflozins), with a special focus on synthetic routes to jardiance (empagliflozin) and its uses. We do hope that young researchers from the field get benefitted from this concise and critical outlook.

Acknowledgement

Dr. RV is thankful to Dr. Ch.V. Rajasekhar, Scrips Pharma for his continued support and encouragement.

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Hao Jiang

As an author who has recently published in the journal "Brain and Neurological Disorders". I am delighted to provide a testimonial on the peer review process, editorial office support, and the overall quality of the journal. The peer review process at Brain and Neurological Disorders is rigorous and meticulous, ensuring that only high-quality, evidence-based research is published. The reviewers are experts in their fields, and their comments and suggestions were constructive and helped improve the quality of my manuscript. The review process was timely and efficient, with clear communication from the editorial office at each stage. The support from the editorial office was exceptional throughout the entire process. The editorial staff was responsive, professional, and always willing to help. They provided valuable guidance on formatting, structure, and ethical considerations, making the submission process seamless. Moreover, they kept me informed about the status of my manuscript and provided timely updates, which made the process less stressful. The journal Brain and Neurological Disorders is of the highest quality, with a strong focus on publishing cutting-edge research in the field of neurology. The articles published in this journal are well-researched, rigorously peer-reviewed, and written by experts in the field. The journal maintains high standards, ensuring that readers are provided with the most up-to-date and reliable information on brain and neurological disorders. In conclusion, I had a wonderful experience publishing in Brain and Neurological Disorders. The peer review process was thorough, the editorial office provided exceptional support, and the journal's quality is second to none. I would highly recommend this journal to any researcher working in the field of neurology and brain disorders.

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Dr Shiming Tang

Dear Agrippa Hilda, Journal of Neuroscience and Neurological Surgery, Editorial Coordinator, I trust this message finds you well. I want to extend my appreciation for considering my article for publication in your esteemed journal. I am pleased to provide a testimonial regarding the peer review process and the support received from your editorial office. The peer review process for my paper was carried out in a highly professional and thorough manner. The feedback and comments provided by the authors were constructive and very useful in improving the quality of the manuscript. This rigorous assessment process undoubtedly contributes to the high standards maintained by your journal.

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Raed Mualem

International Journal of Clinical Case Reports and Reviews. I strongly recommend to consider submitting your work to this high-quality journal. The support and availability of the Editorial staff is outstanding and the review process was both efficient and rigorous.

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Andreas Filippaios

Thank you very much for publishing my Research Article titled “Comparing Treatment Outcome Of Allergic Rhinitis Patients After Using Fluticasone Nasal Spray And Nasal Douching" in the Journal of Clinical Otorhinolaryngology. As Medical Professionals we are immensely benefited from study of various informative Articles and Papers published in this high quality Journal. I look forward to enriching my knowledge by regular study of the Journal and contribute my future work in the field of ENT through the Journal for use by the medical fraternity. The support from the Editorial office was excellent and very prompt. I also welcome the comments received from the readers of my Research Article.

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Dr Suramya Dhamija

Dear Erica Kelsey, Editorial Coordinator of Cancer Research and Cellular Therapeutics Our team is very satisfied with the processing of our paper by your journal. That was fast, efficient, rigorous, but without unnecessary complications. We appreciated the very short time between the submission of the paper and its publication on line on your site.

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Bruno Chauffert

I am very glad to say that the peer review process is very successful and fast and support from the Editorial Office. Therefore, I would like to continue our scientific relationship for a long time. And I especially thank you for your kindly attention towards my article. Have a good day!

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Baheci Selen

"We recently published an article entitled “Influence of beta-Cyclodextrins upon the Degradation of Carbofuran Derivatives under Alkaline Conditions" in the Journal of “Pesticides and Biofertilizers” to show that the cyclodextrins protect the carbamates increasing their half-life time in the presence of basic conditions This will be very helpful to understand carbofuran behaviour in the analytical, agro-environmental and food areas. We greatly appreciated the interaction with the editor and the editorial team; we were particularly well accompanied during the course of the revision process, since all various steps towards publication were short and without delay".

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Jesus Simal-Gandara

I would like to express my gratitude towards you process of article review and submission. I found this to be very fair and expedient. Your follow up has been excellent. I have many publications in national and international journal and your process has been one of the best so far. Keep up the great work.

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Douglas Miyazaki

We are grateful for this opportunity to provide a glowing recommendation to the Journal of Psychiatry and Psychotherapy. We found that the editorial team were very supportive, helpful, kept us abreast of timelines and over all very professional in nature. The peer review process was rigorous, efficient and constructive that really enhanced our article submission. The experience with this journal remains one of our best ever and we look forward to providing future submissions in the near future.

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Dr Griffith

I am very pleased to serve as EBM of the journal, I hope many years of my experience in stem cells can help the journal from one way or another. As we know, stem cells hold great potential for regenerative medicine, which are mostly used to promote the repair response of diseased, dysfunctional or injured tissue using stem cells or their derivatives. I think Stem Cell Research and Therapeutics International is a great platform to publish and share the understanding towards the biology and translational or clinical application of stem cells.

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Dr Tong Ming Liu

I would like to give my testimony in the support I have got by the peer review process and to support the editorial office where they were of asset to support young author like me to be encouraged to publish their work in your respected journal and globalize and share knowledge across the globe. I really give my great gratitude to your journal and the peer review including the editorial office.

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Husain Taha Radhi

I am delighted to publish our manuscript entitled "A Perspective on Cocaine Induced Stroke - Its Mechanisms and Management" in the Journal of Neuroscience and Neurological Surgery. The peer review process, support from the editorial office, and quality of the journal are excellent. The manuscripts published are of high quality and of excellent scientific value. I recommend this journal very much to colleagues.

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S Munshi

Dr.Tania Muñoz, My experience as researcher and author of a review article in The Journal Clinical Cardiology and Interventions has been very enriching and stimulating. The editorial team is excellent, performs its work with absolute responsibility and delivery. They are proactive, dynamic and receptive to all proposals. Supporting at all times the vast universe of authors who choose them as an option for publication. The team of review specialists, members of the editorial board, are brilliant professionals, with remarkable performance in medical research and scientific methodology. Together they form a frontline team that consolidates the JCCI as a magnificent option for the publication and review of high-level medical articles and broad collective interest. I am honored to be able to share my review article and open to receive all your comments.

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Tania Munoz

“The peer review process of JPMHC is quick and effective. Authors are benefited by good and professional reviewers with huge experience in the field of psychology and mental health. The support from the editorial office is very professional. People to contact to are friendly and happy to help and assist any query authors might have. Quality of the Journal is scientific and publishes ground-breaking research on mental health that is useful for other professionals in the field”.

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George Varvatsoulias

Dear editorial department: On behalf of our team, I hereby certify the reliability and superiority of the International Journal of Clinical Case Reports and Reviews in the peer review process, editorial support, and journal quality. Firstly, the peer review process of the International Journal of Clinical Case Reports and Reviews is rigorous, fair, transparent, fast, and of high quality. The editorial department invites experts from relevant fields as anonymous reviewers to review all submitted manuscripts. These experts have rich academic backgrounds and experience, and can accurately evaluate the academic quality, originality, and suitability of manuscripts. The editorial department is committed to ensuring the rigor of the peer review process, while also making every effort to ensure a fast review cycle to meet the needs of authors and the academic community. Secondly, the editorial team of the International Journal of Clinical Case Reports and Reviews is composed of a group of senior scholars and professionals with rich experience and professional knowledge in related fields. The editorial department is committed to assisting authors in improving their manuscripts, ensuring their academic accuracy, clarity, and completeness. Editors actively collaborate with authors, providing useful suggestions and feedback to promote the improvement and development of the manuscript. We believe that the support of the editorial department is one of the key factors in ensuring the quality of the journal. Finally, the International Journal of Clinical Case Reports and Reviews is renowned for its high- quality articles and strict academic standards. The editorial department is committed to publishing innovative and academically valuable research results to promote the development and progress of related fields. The International Journal of Clinical Case Reports and Reviews is reasonably priced and ensures excellent service and quality ratio, allowing authors to obtain high-level academic publishing opportunities in an affordable manner. I hereby solemnly declare that the International Journal of Clinical Case Reports and Reviews has a high level of credibility and superiority in terms of peer review process, editorial support, reasonable fees, and journal quality. Sincerely, Rui Tao.

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Rui Tao

Clinical Cardiology and Cardiovascular Interventions I testity the covering of the peer review process, support from the editorial office, and quality of the journal.

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Khurram Arshad

Clinical Cardiology and Cardiovascular Interventions, we deeply appreciate the interest shown in our work and its publication. It has been a true pleasure to collaborate with you. The peer review process, as well as the support provided by the editorial office, have been exceptional, and the quality of the journal is very high, which was a determining factor in our decision to publish with you.

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Gomez Barriga Maria Dolores

The peer reviewers process is quick and effective, the supports from editorial office is excellent, the quality of journal is high. I would like to collabroate with Internatioanl journal of Clinical Case Reports and Reviews journal clinically in the future time.

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Lin Shaw Chin

Clinical Cardiology and Cardiovascular Interventions, I would like to express my sincerest gratitude for the trust placed in our team for the publication in your journal. It has been a true pleasure to collaborate with you on this project. I am pleased to inform you that both the peer review process and the attention from the editorial coordination have been excellent. Your team has worked with dedication and professionalism to ensure that your publication meets the highest standards of quality. We are confident that this collaboration will result in mutual success, and we are eager to see the fruits of this shared effort.

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Maria Dolores Gomez Barriga

Dear Dr. Jessica Magne, Editorial Coordinator 0f Clinical Cardiology and Cardiovascular Interventions, I hope this message finds you well. I want to express my utmost gratitude for your excellent work and for the dedication and speed in the publication process of my article titled "Navigating Innovation: Qualitative Insights on Using Technology for Health Education in Acute Coronary Syndrome Patients." I am very satisfied with the peer review process, the support from the editorial office, and the quality of the journal. I hope we can maintain our scientific relationship in the long term.

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Dr Maria Dolores Gomez Barriga