Ertugliflozin

Rutas sintéticas y condiciones de reacción: La síntesis de ertugliflozina implica varios pasos, comenzando con la protección del grupo alcohol primario de un compuesto intermedio con un grupo tritilo en presencia de piridina. Esto va seguido de una posterior desprotección con ácido p-toluensulfónico . El proceso también implica el uso de compuestos de Fórmula III, Fórmula IV y Fórmula VII, que están protegidos con grupos protectores adecuados para garantizar una alta pureza y rendimiento .

Métodos de producción industrial: La producción industrial de ertugliflozina sigue rutas sintéticas similares pero a mayor escala. El proceso implica el uso de técnicas y equipos avanzados para garantizar un alto rendimiento y pureza. El uso de productos químicos peligrosos como la piridina se minimiza para garantizar la seguridad y el cumplimiento de las normas industriales .

Degradation Reactions Under Stress Conditions

Ertugliflozin exhibits stability under thermal, photolytic, neutral, and alkaline hydrolysis conditions but degrades in acidic and oxidative environments. These reactions were studied as per ICH guidelines (Q1A–Q1E) to identify degradation products (DPs) and their mechanisms .

Key Degradation Pathways:

• Acid Hydrolysis (1N HCl at 60°C for 48 h) :
  • Forms four degradation products (DP-1 to DP-4) via:
    • Ritter reaction (DP-1: acetonitrile reacts with protonated formaldehyde).
    • Benzyl ether cleavage (DP-2: acid-mediated elimination of the ethoxybenzyl group).
    • Esterification (DP-3: reaction with acetic acid from sugar decomposition).
    • Chlorination (DP-4: SN2 displacement of hydroxymethyl group by chloride) .
• Oxidative Hydrolysis (30% H₂O₂ at RT for 48 h) :
  • Generates DP-5 via oxidative cleavage of the aryl ethoxy group to phenol .

Structural Characterization of Degradation Products

All five degradation products were characterized using UHPLC-MS , HRMS , NMR (1D/2D) , and IR spectroscopy . Key data include:

Data from

Metabolic Reactions

This compound is primarily metabolized via glucuronidation (86%) and minor oxidative pathways (12%) :

• UGT1A9/UGT2B7-mediated glucuronidation : Forms inactive metabolites M5a (2-O-β-glucuronide) and M5c (3-O-β-glucuronide).
• CYP3A4-mediated oxidation : Produces hydroxy (M1/M3) and desethyl (M2) metabolites .

Synthetic Reactions

The commercial synthesis of this compound involves:

• Cocrystallization : this compound is stabilized as a 1:1 cocrystal with L-pyroglutamic acid to enhance solubility and stability .
• Key intermediates : Protection/deprotection steps using formaldehyde and acetonitrile under acidic conditions .

Stability in Formulations

• pH-dependent solubility : Sparingly soluble in water (0.64–0.74 mg/mL at physiological pH) .
• Humidity-induced dissociation : The cocrystal partially converts to amorphous this compound under high humidity but remains bioequivalent .

Interaction with Analytical Reagents

This compound reacts with formaldehyde and dichloromethane during stress testing, leading to DP-1 and DP-4 formation .

Clinical Efficacy in Type 2 Diabetes Management

Ertugliflozin has demonstrated significant reductions in HbA1c levels across various studies. In a pivotal phase 3 trial, participants showed a mean reduction in HbA1c of 0.6% to 0.9% compared to placebo after 52 weeks of treatment .

Key Clinical Trials

• VERTIS Trials : These trials evaluated the efficacy and safety of this compound in patients with T2DM and established cardiovascular disease. The results indicated that this compound was noninferior to placebo concerning major adverse cardiovascular events, but it did show trends toward reduced hospitalization for heart failure .
• Long-term Efficacy : A study assessing long-term outcomes reported sustained reductions in HbA1c over two years, with patients on higher doses (15 mg) showing more significant improvements compared to lower doses (5 mg) .

Cardiovascular Benefits

This compound has been associated with cardiovascular benefits beyond glycemic control. The VERTIS CV trial highlighted that this compound reduced the risk of hospitalization for heart failure by approximately 30% compared to placebo .

Cardiovascular Outcomes Summary

Renal Outcomes

Recent studies have also explored the renal protective effects of this compound. It has shown promise in improving renal outcomes in patients with chronic kidney disease (CKD) and T2DM, demonstrating a reduction in the progression of kidney disease markers .

Renal Outcomes Summary

Safety Profile

While this compound is generally well-tolerated, some adverse effects have been noted, including an increased risk of genital mycotic infections and urinary tract infections . However, these side effects are manageable and do not outweigh the benefits seen in glycemic control and cardiovascular health.

Combination Therapy

This compound can be used as monotherapy or in combination with other antidiabetic agents such as metformin or sitagliptin. Clinical trials have shown that such combinations can lead to enhanced glycemic control while minimizing the risk of hypoglycemia associated with insulin or sulfonylureas .

La ertugliflozina ejerce sus efectos inhibiendo el cotransportador 2 de sodio-glucosa (SGLT2) en los riñones. Esta inhibición previene la reabsorción de glucosa del filtrado glomerular, lo que lleva a una mayor excreción de glucosa urinaria y una reducción de los niveles de glucosa en sangre . Los objetivos moleculares implicados en este proceso incluyen las proteínas SGLT2 ubicadas en los túbulos proximales de los riñones .

La ertugliflozina forma parte de la clase de medicamentos inhibidores de SGLT2, que también incluye canagliflozina, dapagliflozina y empagliflozina. En comparación con estos compuestos, la ertugliflozina ha mostrado una eficacia similar en la reducción de los niveles de glucosa en sangre, pero puede tener un perfil de seguridad y efectos secundarios diferente . Por ejemplo, se ha encontrado que la ertugliflozina tiene un menor riesgo de causar infecciones del tracto urinario en comparación con algunos otros inhibidores de SGLT2 .

• Canagliflozina
• Dapagliflozina
• Empagliflozina
• Bexagliflozina

Ertugliflozin is a sodium-glucose cotransporter-2 (SGLT2) inhibitor that plays a significant role in the management of type 2 diabetes mellitus (T2DM). This compound enhances glycemic control by promoting urinary glucose excretion, thereby lowering blood glucose levels. This article delves into the biological activity of this compound, highlighting its pharmacokinetics, mechanisms of action, clinical efficacy, and safety profile based on diverse research findings.

This compound selectively inhibits SGLT2, a protein responsible for the reabsorption of glucose in the kidneys. By blocking this transporter, this compound increases urinary glucose excretion and decreases blood glucose levels. The selectivity of this compound for SGLT2 over SGLT1 is significant, with an IC50 value of 0.877 nM for SGLT2 compared to 1960 nM for SGLT1, indicating a greater than 2000-fold selectivity .

Pharmacokinetics

This compound exhibits favorable pharmacokinetic properties:

• Bioavailability : Approximately 100% when administered orally.
• Peak Concentration : Achieved within 1-2 hours post-dose.
• Half-life : Approximately 16.6 hours in T2DM patients, supporting once-daily dosing.
• Metabolism : Primarily metabolized by UGT1A9 and UGT2B7 through O-glucuronidation into inactive metabolites .

Clinical Efficacy

This compound has been evaluated in multiple clinical trials assessing its efficacy as monotherapy and in combination with other antidiabetic agents. Key findings include:

• VERTIS-CV Trial : Demonstrated a reduction in hospitalizations for heart failure among patients treated with this compound compared to placebo .
• Long-term Studies : A 104-week study showed significant reductions in HbA1c levels (up to -0.84% at week 104) and improvements in fasting plasma glucose (FPG) and body weight .

Table 1: Summary of Key Clinical Trials Involving this compound

Safety Profile

While this compound is generally well-tolerated, it is associated with some adverse effects:

• Genital Mycotic Infections : Higher incidence reported among patients treated with this compound compared to placebo.
• Diabetic Ketoacidosis : Rare cases have been documented, particularly in patients with underlying conditions such as Latent Autoimmune Diabetes of Adulthood (LADA) .
• Bone Mineral Density : Minimal changes observed; however, some reductions were noted at the hip region after long-term use .

Case Studies

Several case studies have highlighted the real-world efficacy and safety of this compound:

• Case Study on Cardiovascular Outcomes : A patient with established cardiovascular disease showed improved cardiovascular outcomes after initiating treatment with this compound alongside standard diabetes management.
• Long-term Management Case : A patient inadequately controlled on metformin alone achieved target HbA1c levels after adding this compound to their regimen over a period of six months.