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Empagliflozin
- Iupac Name：(2S,3R,4R,5S,6R)-2-[4-chloro-3-[[4-[(3S)-oxolan-3-yl]oxyphenyl]methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol
- CAS No.: 864070-44-0
- Molecular Weight：450.9
- Modify Date.: 2022-11-25 01:11
- Introduction: Empagliflozin(trade name Jardiance) is an inhibitor of the sodium glucose co-transporter-2 (SGLT-2), and causes sugar in the blood to be excreted by the kidneys and eliminated in urine. On August 1, 2014, the Food and Drug Administration (FDA) officially approved the drug for the treatment of type 2 diabetes, to improve and control blood glucose of adults. Empagliflozin is the third SGLT-2 inhibiting drugs approved by FDA. Another two SGLT-2 inhibitor drugs, canagliflozin and dapagliflozin, belonging to Johnson Pharmaceuticals, AstraZeneca and Bristol-Myers Squibb respectively, are approved by FDA in November 2013 and January 2014 respectively. The new drug Empagliflozin’s application to FDA can be described as twists and turns. In March 2014, due to a large particle contamination incident at the empagliflozin production plant in Boehringer, the application of new drug submitted by the Boehringer-Eli Lilly Alliance was rejected by FDA. In June 2014, after reviewing the summary and material submitted by Boehring in March, confirming that the quality management and compliance system of the Boehring drug production facility was acceptable, FDA withdrew the previously issued warning letter. The Boehringer-Eli Lilly Alliance also filed an application with the FDA on June 17th.
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1. Names and Identifiers
- 1.1 Name
- Empagliflozin
- 1.2 Synonyms
(1S)-1,5-Anhydro-1-(4-chloro-3-{4-[(3S)-tetrahydro-3-furanyloxy]benzyl}phenyl)-D-glucitol (1S)-1,5-Anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-D-glucitol (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((S)-tetrahydrofuran-3-yloxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol BI 10773 BI10773 BI-10773 CS-0940 CS-798 D-Glucitol, 1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-, (1S)- EMPAGLIFLBZIN Empaglifloin EMpagliflozin Empagliflozin API Empagliflozin(W.S) Jardiance X5927
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- 1.3 CAS No.
- 864070-44-0
- 1.4 CID
- 11949646
- 1.5 EINECS(EC#)
- 620-176-8
- 1.6 Molecular Formula
- C23H27ClO7 (isomer)
- 1.7 Inchi
- InChI=1S/C23H27ClO7/c24-18-6-3-14(23-22(28)21(27)20(26)19(11-25)31-23)10-15(18)9-13-1-4-16(5-2-13)30-17-7-8-29-12-17/h1-6,10,17,19-23,25-28H,7-9,11-12H2/t17-,19+,20+,21-,22+,23-/m0/s1
- 1.8 InChIkey
- OBWASQILIWPZMG-QZMOQZSNSA-N
- 1.9 Canonical Smiles
- C1COCC1OC2=CC=C(C=C2)CC3=C(C=CC(=C3)C4C(C(C(C(O4)CO)O)O)O)Cl
- 1.10 Isomers Smiles
- C1COC[C@H]1OC2=CC=C(C=C2)CC3=C(C=CC(=C3)[C@H]4[C@@H]([C@H]([C@@H]([C@H](O4)CO)O)O)O)Cl
2. Properties
- 2.1 Density
- 1.398
- 2.1 Boiling point
- 665℃
- 2.1 Refractive index
- 1.628 (Predicted)
- 2.1 Flash Point
- 356℃
- 2.1 Precise Quality
- 450.14500
- 2.1 PSA
- 108.61000
- 2.1 logP
- 1.61340
- 2.1 Solubility
- [0.28]
- 2.2 Color/Form
- Powder
- 2.3 pKa
- 13.23±0.70(Predicted)
- 2.4 Water Solubility
- [0.28]
- 2.5 StorageTemp
- 2-8°C
3. Use and Manufacturing
- 3.1 Definition
- ChEBI: A C-glycosyl compound consisting of a beta-glucosyl residue having a (4-chloro-3-{4-[(3S)-tetrahydrofuran-3-yloxy]benzyl}phenyl group at the anomeric centre. A sodium-glucose co-transporter 2 inhibitor ued as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
- 3.2 Usage
- Empagliflozin is a novel, potent and selective SGLT-2 inhibitor, improves glycaemic control and features of metabolic syndrome in diabetic rats.
4. Safety and Handling
- 4.1 Hazard Declaration
- H361
- 4.1 Caution Statement
- P201, P202, P281, P308+P313, P405, P501
5. MSDS
2.Hazard identification
2.1 Classification of the substance or mixture
no data available
2.2 GHS label elements, including precautionary statements
| Pictogram(s) | no data available |
| Signal word | no data available |
| Hazard statement(s) | no data available |
| Precautionary statement(s) | |
| Prevention | no data available |
| Response | no data available |
| Storage | no data available |
| Disposal | no data available |
2.3 Other hazards which do not result in classification
no data available
6. Synthesis Route
864070-44-0Total: 7 Synthesis Route
8. Other Information
- 8.0 Description
- Empagliflozin(trade name Jardiance) is an inhibitor of the sodium glucose co-transporter-2 (SGLT-2), and causes sugar in the blood to be excreted by the kidneys and eliminated in urine. On August 1, 2014, the Food and Drug Administration (FDA) officially approved the drug for the treatment of type 2 diabetes, to improve and control blood glucose of adults. Empagliflozin is the third SGLT-2 inhibiting drugs approved by FDA. Another two SGLT-2 inhibitor drugs, canagliflozin and dapagliflozin, belonging to Johnson Pharmaceuticals, AstraZeneca and Bristol-Myers Squibb respectively, are approved by FDA in November 2013 and January 2014 respectively. The new drug Empagliflozin’s application to FDA can be described as twists and turns. In March 2014, due to a large particle contamination incident at the empagliflozin production plant in Boehringer, the application of new drug submitted by the Boehringer-Eli Lilly Alliance was rejected by FDA. In June 2014, after reviewing the summary and material submitted by Boehring in March, confirming that the quality management and compliance system of the Boehring drug production facility was acceptable, FDA withdrew the previously issued warning letter. The Boehringer-Eli Lilly Alliance also filed an application with the FDA on June 17th.
- View all
- 8.1 Clinical research
- FDA approval of empagliflozin(Jardiance) was based on the results of seven clinical trials conducted in nearly 4,500 patients with type 2 diabetes mellitus. Compared to the placebo group, all patients taking empagliflozin(Jardiance) had a significantly lower HbA1c level. The most common adverse reactions are urinary tract infections and female reproductive system infections.
On March 21, 2014, European Medicines Agency (EMA) Commission on Human Medicines recommended the approval of the sodium glucose co-transporter-2 (SGLT2) inhibitor (empagliflozin) for the treatment of adult type 2 diabetes mellitus.
On May 23, 2014, European Medicines Agency (EMA) approved for empagliflozin’s listing in Europe.
On June 16, 2014, the Boehringer-Erya Diabetes Federation released the latest data of empagliflozin Phase II clinical trials at the 74th American Diabetes Association Science Conference (ADA2014). In a two-year study, empagliflozin or glimepiride was used in the treatment of adult patients with type 2 diabetes based on metformin. The results showed that empagliflozin(Jardiance) reduced HbA1c more significantly compared with glimepiride, while the effect of weight and blood pressure treatment are equivalent with glimepiride. Another 52-week study was conducted in patients with type 2 diabetes who were still unable to adequately control blood glucose levels with high doses of insulin (with or without metformin). The results showed that compared with placebo, Jardiance significantly reduced blood glucose levels and weight, and reduced the dose of insulin, with Jardiance or placebo on a daily basis with multiple injections of insulin. In both studies, the safety of empagliflozin was consistent with previous studies.
FDA-related reports write that the drug should not be used in the following types of patients: type 1 diabetes, elevated blood or urine ketones (diabetic ketoacidosis), severe kidney damage, end-stage renal disease or dialysis patients. The most common side effects are urinary tract infections and female genital infections.
Empagliflozin can cause dehydration and lead to decreased blood pressure, resulting in patients with dizziness or fainting and decreased renal function. The risk of older patients, especially those with impaired renal function and diuretics, appears to be greater.
FDA requires Boehring and Eli Lilly to conduct four post-marketing studies: complete ongoing cardiovascular outcome trials, pediatric pharmacokinetics and pharmacodynamics trials, pediatric safety and efficacy trials, toxicity test for the drug (especially effect for renal function, bone and growth and development) - View all
- 8.2 Precautions
- Do NOT use empagliflozin if:
- you are allergic to any ingredient in empagliflozin
- you have type 1 diabetes
- you have high blood or urine ketone levels (diabetic ketoacidosis)
- you have severe kidney problems or are on dialysis
- 8.3 References
- https://en.wikipedia.org/wiki/Empagliflozin
https://www.drugs.com/cdi/empagliflozin.html
- 8.4 Description
- Empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, was originally discovered by Boehringer Ingelheim and codeveloped and co-marketed through research collaboration with Eli Lilly and Co. It was first approved by European Medicine Agency (EMA) in May 2014, followed by the approval of the US FDA in August 2014. SGLT2 inhibitors are anewclass of glucose-lowering agents developed for the treatment of type 2 diabetes mellitus, which have a mechanism of action that is independent of pancreatic b-cell function or the degree of insulin resistance. Consequently, SGLT2 inhibitors have the potential to be of use not only as standalone therapy but also in combination with any of the existing classes of glucose-lowering agents, including insulin. Empagliflozin selectively inhibits SGLT2, which in turn prevents glucose reabsorption by excreting excess glucose in the urine.
- 8.5 Uses
- Empagliflozin is a novel, potent and selective SGLT-2 inhibitor, improves glycaemic control and features of metabolic syndrome in diabetic rats.
- 8.6 Definition
- ChEBI: A C-glycosyl compound consisting of a beta-glucosyl residue having a (4-chloro-3-{4-[(3S)-tetrahydrofuran-3-yloxy]benzyl}phenyl group at the anomeric centre. A sodium-glucose co-transporter 2 inhibitor u ed as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
- 8.7 Clinical Use
- Selective and reversible inhibitor of sodium-glucose co-transporter 2:
Treatment of type 2 diabetes
- 8.8 Side effects
- Empagliflozin had a low incidence of adverse reactions. Compared with the placebo group, the incidence of common adverse reactions was 2%, including urinary tract infection, female reproductive system fungal infection, upper respiratory tract infection, polyuria, dyslipidemia (dose-related low-density lipoprotein increased), arthralgia, fungal infection of male reproductive system, hypoglycemia (the incidence of hypoglycemia increased when empagliflozin was combined with insulin or sulfonylurea hypoglycemic drugs), nausea. Other adverse reactions less than 2% were common in thirst (polydipsia, polydipsia), hypovolemia, and renal dysfunction.
- 8.9 Chemical Synthesis
- Commercial 5-iodo-2-chlorobenzoic acid (97) was first converted to the corresponding acid chloride, prior to subjection to commercially available fluorobenzene (98) under Friedel–Crafts conditions to generate the desired fluorobenzophenone 99 in 94% yield after isolation by recrystallization from aqueous isopropanol. The fluorobenzophenone (99) was then reacted with commercially available (S)-3-hydroxytetrahydrofuran (100) and potassium tertbutoxide in THF to afford ethereal benzophenone 101. Next, removal of the ketone functionality within 101 was achieved through the use of 1,1,3,3-tetramethyldisiloxane (TMDS) in the presence of aluminum chloride in toluene to deliver diaryl iodide 102. This iodide was subsequently converted to the corresponding Grignard reagent and subjected to gluconolactone 103, giving rise to an intermediate lactol which was then sequentially treated with aqueous citric acid, methanolic HCl, and triethylsilyl hydride and aluminum trichloride to ultimately furnish empagliflozin (XIII) in 73% yield across the four-step protocol.
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- 8.10 Drug interactions
- Potentially hazardous interactions with other drugs None known
- 8.11 Metabolism
- In vitro studies suggested that the main route of metabolism is glucuronidation by the uridine 5'-diphospho-glucuronosyltransferases UGT2B7, UGT1A3, UGT1A8, and UGT1A9
Following administration of oral [14C]-empagliflozin solution to healthy volunteers, approximately 96% of the drug-related radioactivity was eliminated in faeces (41%) or urine (54%). The majority of drug-related radioactivity recovered in faeces was unchanged parent drug and approximately half of drug-related radioactivity excreted in urine was unchanged parent drug
9. Computational chemical data
- Molecular Weight: 450.9g/mol
- Molecular Formula: C23H27ClO7
- Compound Is Canonicalized: True
- XLogP3-AA: 2
- Exact Mass: 450.1445309
- Monoisotopic Mass: 450.1445309
- Complexity: 558
- Rotatable Bond Count: 6
- Hydrogen Bond Donor Count: 4
- Hydrogen Bond Acceptor Count: 7
- Topological Polar Surface Area: 109
- Heavy Atom Count: 31
- Defined Atom Stereocenter Count: 6
- Undefined Atom Stereocenter Count: 0
- Defined Bond Stereocenter Count: 0
- Undefined Bond Stereocenter Count: 0
- Isotope Atom Count: 0
- Covalently-Bonded Unit Count: 1
- CACTVS Substructure Key Fingerprint: AAADceB4OAAEAAAAAAAAAAAAAAAAASAAAAA0YIAAAAAAAAABQAAAGgIACAAADBagmCIwBoAABgCAAiBCAAACCAAgJQAIiAAGCogNNiKFMxqCeCClwBELqAfA4PQOJAACAAABAABIAAQAAAIAAAAAAAAAAA==
10. Question & Answer
-
Empagliflozin, a sodium-dependent glucose transporter 2 (SGLT-2) inhibitor, is known for its ability to lower blood glucose levels by inhibiting the reabsorption of glucose in the kidneys, leading to ..
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Overview Empagliflozin, jointly developed by Boehringer Ingelheim and Eli Lilly, is a type 2 sodium glucose cotransporter (SGLT-2) inhibitor[1]. This new hypoglycemic drug works by inhibiting the expr..
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In a new study, researchers from St. Michael's Hospital in Toronto, Western University, and Robarts Research Institute have revealed how a class of drugs that helps regulate blood sugar in type 2 diab..
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In February 2015, the US FDA approved the market application for a new combination antidiabetic drug called Glyxambi (Empagliflozin / Linagliptin) for adjunctive therapy in adult patients with type 2 ..
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