Ertugliflozin

Synthetic Routes and Reaction Conditions: The synthesis of ertugliflozin involves multiple steps, starting with the protection of the primary alcohol moiety of an intermediate compound with a trityl group in the presence of pyridine. This is followed by subsequent deprotection with p-toluenesulfonic acid . The process also involves the use of compounds of Formula III, Formula IV, and Formula VII, which are protected with suitable protecting groups to ensure high purity and yield .

Industrial Production Methods: Industrial production of this compound follows similar synthetic routes but on a larger scale. The process involves the use of advanced techniques and equipment to ensure high yield and purity. The use of hazardous chemicals like pyridine is minimized to ensure safety and compliance with industrial standards .

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 .

Ertugliflozin exerts its effects by inhibiting the sodium-glucose cotransporter 2 (SGLT2) in the kidneys. This inhibition prevents the reabsorption of glucose from the glomerular filtrate, leading to increased urinary glucose excretion and reduced blood glucose levels . The molecular targets involved in this process include the SGLT2 proteins located in the proximal tubules of the kidneys .

Ertugliflozin is part of the SGLT2 inhibitor class of medications, which also includes canagliflozin, dapagliflozin, and empagliflozin. Compared to these compounds, this compound has shown similar efficacy in lowering blood glucose levels but may have a different safety and side effect profile . For instance, this compound has been found to have a lower risk of causing urinary tract infections compared to some other SGLT2 inhibitors .

• Canagliflozin
• Dapagliflozin
• Empagliflozin
• Bexagliflozin

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.