Empagliflozin
[CAS 864070-44-0]

Identification

• Classification: API >> Hormone and endocrine-regulating drugs >> Pancreatic hormones and other blood sugar regulating drugs
• Name: Empagliflozin
• Synonyms: BI 10773; (1S)-1,5-Anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-D-glucitol
• Molecular Formula: C₂₃H₂₇ClO₇
• Molecular Weight: 450.91
• CAS Registry Number: 864070-44-0
• EC Number: 620-176-8
• 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

Properties

• Density: 1.4±0.1 g/cm³ Calc.^*
• Boiling point: 664.5±55.0 °C 760 mmHg (Calc.)^*
• Flash point: 355.7±31.5 °C (Calc.)^*
• Solubility: DMSO: 41mg/mL (Expl.)
• Index of refraction: 1.628 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS07;GHS08 Warning
• Risk Statements: H302-H361-H362
• Safety Statements: P203-P260-P263-P264-P270-P280-P301+P317-P318-P330-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Reproductive toxicity	Repr.	2	H361
Reproductive toxicity	Lact.	-	H362
Acute toxicity	Acute Tox.	4	H302

Discovery and Applications

Empagliflozin is a synthetic small-molecule drug that belongs to the class of sodium–glucose cotransporter 2 (SGLT2) inhibitors. It is used clinically in the treatment of type 2 diabetes mellitus and has also been shown to provide cardiovascular and renal benefits in appropriate patient populations.

Structurally, empagliflozin is a C-aryl glucoside, meaning it contains a glucose-derived sugar unit linked directly to an aromatic aglycone through a stable carbon–carbon bond rather than a more labile oxygen glycosidic linkage. This C–C bond is a key structural feature that increases metabolic stability compared with natural O-glycosides.

The glucose portion of the molecule is a modified β-D-glucopyranose in a six-membered chair conformation. Multiple hydroxyl groups are present on the sugar ring, creating a highly polar region capable of extensive hydrogen bonding. These hydroxyl groups are essential for recognition by the SGLT2 transporter, which normally binds glucose and related structures.

Attached to the anomeric carbon of the glucose is a substituted biphenyl-type aromatic system. This hydrophobic aglycone contains two aromatic rings with various substituents that enhance binding affinity within the SGLT2 protein binding pocket. The aromatic portion contributes significantly to lipophilicity and membrane permeability.

A distinguishing feature of empagliflozin is the presence of a chloro-substituted aromatic ring within the aglycone. Halogen substituents such as chlorine exert electron-withdrawing inductive effects and increase hydrophobic interactions with target proteins. These interactions improve binding strength and selectivity for SGLT2 over related transporters such as SGLT1.

The molecule contains multiple hydroxyl groups on the glucose moiety, which are critical for forming hydrogen bonds with amino acid residues in the SGLT2 binding site. These interactions mimic the natural substrate, D-glucose, allowing empagliflozin to act as a competitive inhibitor of glucose reabsorption in the renal proximal tubules.

Mechanistically, empagliflozin inhibits SGLT2, a sodium-dependent glucose transporter responsible for reabsorbing the majority of filtered glucose in the kidney. By blocking this transporter, empagliflozin reduces renal glucose reabsorption, leading to increased urinary glucose excretion and lowered blood glucose levels in patients with hyperglycemia.

From a physicochemical perspective, empagliflozin is amphiphilic. The glucose-derived region is highly hydrophilic due to multiple hydroxyl groups, while the aromatic aglycone contributes strong hydrophobic character. This balance supports both aqueous solubility (often formulation-dependent) and membrane permeability.

The C-aryl glycosidic bond is chemically stable under physiological conditions and resistant to enzymatic hydrolysis, unlike typical O-glycosides. This stability contributes to the compound’s oral bioavailability and metabolic durability.

The aromatic region of empagliflozin is relatively rigid and contributes to a defined three-dimensional binding conformation. The glucose moiety adopts a chair conformation that closely resembles natural glucose, which is important for recognition by the transporter protein.

Chemically, the hydroxyl groups on the sugar are the most reactive sites, capable of forming esters or ethers under synthetic modification conditions. However, in vivo they primarily function as hydrogen bond donors and acceptors rather than reactive functional groups. The aromatic portion is largely chemically stable under physiological conditions.

Overall, empagliflozin is a C-aryl glucoside SGLT2 inhibitor composed of a glucose-derived hydrophilic domain linked through a stable carbon–carbon bond to a hydrophobic substituted aromatic system. Its structure is optimized for selective inhibition of renal glucose reabsorption, combining glucose mimicry with enhanced metabolic stability and transporter affinity.

References

2026. Effects of empagliflozin on cardiac function and cardiorespiratory fitness in people with type 2 diabetes: a randomised controlled trial. Cardiovascular Diabetology – Endocrinology Reports.
DOI: 10.1186/s40842-026-00281-9

2026. More than Glucose Elimination: Additional Benefits of SGLT2 Inhibitors in Glomerular Diseases. Drugs.
DOI: 10.1007/s40265-026-02286-1

2026. Metformin and beyond: glucose-lowering therapy as a potential modulator of abdominal aortic aneurysm growth and stability- systematic review with narrative synthesis. Cardiovascular Diabetology – Endocrinology Reports.
DOI: 10.1186/s40842-026-00275-7