Ertugliflozin

合成経路および反応条件： エルツグリフロジンの合成は、ピリジンの存在下で、中間体の第一級アルコール部分をトリチル基で保護することから始まる、複数の段階を伴います。 続いて、p-トルエンスルホン酸による脱保護が行われます . このプロセスには、式III、式IV、および式VIIの化合物の使用も含まれており、これらの化合物は、高い純度と収率を確保するために、適切な保護基で保護されています .

工業生産方法： エルツグリフロジンの工業生産は、同様の合成経路に従いますが、より大規模に行われます。このプロセスには、高い収率と純度を確保するために、高度な技術と機器の使用が含まれています。 ピリジンなどの危険な化学物質の使用は、安全性と産業基準への準拠を確保するために最小限に抑えられています .

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 .

エルツグリフロジンは、腎臓のナトリウム-グルコース共輸送体2（SGLT2）を阻害することにより、その効果を発揮します。 この阻害は、糸球体ろ過液からのグルコースの再吸収を防ぎ、尿中へのグルコース排泄量を増加させ、血糖値を低下させます . このプロセスに関与する分子標的は、腎臓の近位尿細管に位置するSGLT2タンパク質です .

エルツグリフロジンは、カナグリフロジン、ダパグリフロジン、エンパグリフロジンなども含まれるSGLT2阻害剤クラスの薬剤に属します。 これらの化合物と比較して、エルツグリフロジンは血糖値を低下させる効果が同等であることが示されていますが、安全性と副作用のプロファイルが異なる可能性があります . たとえば、エルツグリフロジンは、他のいくつかのSGLT2阻害剤と比較して、尿路感染症を引き起こすリスクが低いことがわかっています .

• カナグリフロジン
• ダパグリフロジン
• エンパグリフロジン
• ベクサグリフロジン

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.