Saxagliptin hydrochloride

合成路线和反应条件： 沙格列汀盐酸盐的合成涉及几个关键步骤。一种常见的方法是在偶联试剂的存在下偶联两种氨基酸衍生物。 （S）-(+)-对甲苯磺酰胺、乙醇钛(IV)和金刚烷-1-甲醛在羟基苯并三唑和EDC (1-乙基-3-(3-二甲基氨基丙基)碳二亚胺)存在下的酰胺偶联是一个关键步骤 .

工业生产方法： 沙格列汀盐酸盐的工业生产通常采用高效液相色谱 (HPLC) 来定量和验证该化合物。 这种方法确保了最终产品的纯度和质量 .

反应类型： 沙格列汀盐酸盐会发生各种化学反应，包括：

氧化： 此反应涉及添加氧或去除氢。

还原： 此反应涉及添加氢或去除氧。

取代： 此反应涉及用另一种原子或原子团取代一个原子或原子团。

常用试剂和条件： 这些反应中常用的试剂包括高锰酸钾等氧化剂、硼氢化钠等还原剂以及卤素等取代试剂。 这些反应的条件通常需要控制温度和pH值，以确保达到预期结果 .

主要产物： 这些反应产生的主要产物包括各种中间体，这些中间体对于沙格列汀盐酸盐的合成至关重要。 然后将这些中间体进一步加工以获得最终化合物 .

Primary Use in Type 2 Diabetes Mellitus

Saxagliptin is primarily indicated for use as an adjunct to diet and exercise in adults with type 2 diabetes. It has shown effectiveness in lowering blood sugar levels, improving glycemic control as measured by reductions in glycated hemoglobin (HbA1c) levels. Clinical studies have demonstrated that saxagliptin can lead to significant improvements in fasting plasma glucose and postprandial glucose levels across diverse patient populations, including those with varying cardiovascular risk factors .

Combination Therapy

Recent studies have explored the efficacy of saxagliptin when used in combination with other treatments:

• With Insulin : Saxagliptin has been shown to be effective in patients already on insulin therapy, providing additional glycemic control .
• With Vitamin D : A study indicated that saxagliptin combined with vitamin D could help preserve beta-cell function in adult-onset type 1 diabetes, demonstrating a potential role beyond type 2 diabetes management .

Cardiovascular Implications

Research has suggested that saxagliptin may have beneficial effects on cardiovascular health. In various clinical trials, it was found to be well-tolerated and associated with improved glycemic control without significant adverse cardiovascular events, making it a suitable option for diabetic patients with cardiovascular concerns .

Renal Impairment Considerations

Saxagliptin's pharmacokinetics are affected by renal function. Studies indicate that dosage adjustments may be necessary for patients with renal impairment to avoid increased exposure and potential side effects. This highlights the importance of individualized treatment plans based on renal function .

Clinical Trials Overview

A comprehensive review of clinical trials involving saxagliptin reveals consistent findings regarding its efficacy and safety:

Side Effects

While generally well-tolerated, saxagliptin can cause side effects such as:

• Headache
• Nasopharyngitis
• Gastrointestinal issues
• Rarely, pancreatitis or severe allergic reactions .

Case Study: Saxagliptin and Beta-Cell Function Preservation

A multicenter randomized trial evaluated the impact of saxagliptin combined with vitamin D on beta-cell function in patients with adult-onset type 1 diabetes. The study demonstrated that this combination therapy led to a statistically significant preservation of C-peptide levels over a 24-month period compared to conventional therapy alone, suggesting potential benefits for patients beyond standard diabetes management .

Observational Study: Hospitalized Heart Failure Risk

An observational study assessed the risk of hospitalized heart failure among new users of saxagliptin compared to other DPP-4 inhibitors. The findings indicated no significant increase in heart failure risk among saxagliptin users, reinforcing its safety profile in diabetic patients with pre-existing heart conditions .

沙格列汀盐酸盐通过抑制二肽基肽酶-4 (DPP-4) 酶发挥作用。这种抑制增加了肠降血糖素激素（如胰高血糖素样肽-1 (GLP-1) 和葡萄糖依赖性胰岛素促分泌多肽 (GIP)）的水平。 这些激素通过增加胰岛素分泌和减少肝脏胰高血糖素分泌来帮助降低血糖水平 .

相似化合物：

二甲双胍： 另一种降糖药，可以提高胰岛素敏感性。

司美格鲁肽： 一种 GLP-1 受体激动剂，模拟肠降血糖素激素的作用。

比较：

沙格列汀盐酸盐与二甲双胍： 沙格列汀盐酸盐通过抑制 DPP-4 发挥作用，而二甲双胍则提高胰岛素敏感性。

沙格列汀盐酸盐与司美格鲁肽： 两种药物都提高肠降血糖素激素水平，但司美格鲁肽是 GLP-1 受体激动剂，而沙格列汀盐酸盐是 DPP-4 抑制剂。

沙格列汀盐酸盐因其独特的作用机制及其在治疗2型糖尿病的联合疗法中的有效性而脱颖而出。

Metformin: Another antidiabetic drug that improves insulin sensitivity.

Semaglutide: A GLP-1 receptor agonist that mimics the effects of incretin hormones.

Comparison:

Saxagliptin Hydrochloride vs. Metformin: this compound works by inhibiting DPP-4, while Metformin improves insulin sensitivity.

This compound vs. Semaglutide: Both drugs increase the levels of incretin hormones, but Semaglutide is a GLP-1 receptor agonist, while this compound is a DPP-4 inhibitor.

This compound stands out due to its specific mechanism of action and its effectiveness in combination therapies for type 2 diabetes mellitus.

Saxagliptin hydrochloride is a dipeptidyl peptidase-4 (DPP-4) inhibitor primarily used in the management of type 2 diabetes mellitus (T2DM). Its biological activity is characterized by its ability to enhance glycemic control through various mechanisms, including the modulation of incretin hormones. This article explores the biological activity of saxagliptin, supported by data tables, case studies, and detailed research findings.

Saxagliptin acts by inhibiting the DPP-4 enzyme, which is responsible for the degradation of incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). By preventing the breakdown of these hormones, saxagliptin increases their levels in circulation, leading to:

• Increased Insulin Secretion : Saxagliptin enhances insulin release from pancreatic beta cells in response to elevated blood glucose levels.
• Decreased Glucagon Secretion : It reduces glucagon secretion from pancreatic alpha cells, which helps lower hepatic glucose production.
• Improved Glycemic Control : The overall effect is a reduction in fasting plasma glucose and postprandial glucose levels.

The selectivity of saxagliptin for DPP-4 over other DPP enzymes (DPP-8 and DPP-9) is notable, with a 400-fold and 950-fold selectivity, respectively . This selectivity contributes to its favorable safety profile, minimizing adverse effects associated with non-selective DPP inhibition.

Pharmacokinetics

Saxagliptin exhibits first-order kinetics with a median time to peak plasma concentration (Tmax) of approximately 2 hours after oral administration. The elimination half-life is about 2.5 hours for saxagliptin and 3.1 hours for its active metabolite M2 . Key pharmacokinetic parameters are summarized in Table 1.

Clinical Efficacy

Saxagliptin has demonstrated significant efficacy in improving glycemic control in various clinical settings:

• Monotherapy : In clinical trials, saxagliptin reduced HbA1c levels by approximately 0.7% to 0.9% compared to placebo .
• Combination Therapy : When used in combination with metformin or sulfonylureas, saxagliptin showed enhanced efficacy without increasing the risk of hypoglycemia .

Case Study Findings

A recent multi-center randomized controlled trial investigated the effects of saxagliptin combined with vitamin D on β-cell preservation in T2DM patients. Results indicated that participants receiving saxagliptin plus vitamin D had a significant preservation of β-cell function compared to those on conventional therapy alone:

• C-peptide AUC Change at 24 Months :
  • Saxagliptin + Vitamin D: -276 pmol/L
  • Saxagliptin Alone: -314 pmol/L
  • Conventional Therapy: -419 pmol/L

The proportion of participants showing a ΔC-peptide response was significantly higher in the saxagliptin plus vitamin D group (57.6%) compared to conventional therapy (37.2%) .

Safety Profile

Saxagliptin is generally well-tolerated, with a low incidence of hypoglycemia and weight neutrality observed across clinical trials. Adverse effects are comparable to placebo, making it a favorable option for T2DM management .

Q. How can researchers optimize analytical methods for simultaneous quantification of Saxagliptin hydrochloride in combination therapies (e.g., with Metformin or Dapagliflozin)?

Answer:
Researchers should prioritize chromatographic techniques such as HPTLC or RP-HPLC due to their specificity and reproducibility. For HPTLC, a validated method using silica gel plates with a mobile phase of acetonitrile:1% ammonium acetate (9:1 v/v) and detection at 210 nm enables simultaneous analysis of Saxagliptin (SAX), Metformin (MET), and Dapagliflozin (DAP) with linear ranges of 0.25–10 μg/band (SAX/DAP) and 0.25–25 μg/band (MET) . For HPLC, a C18 column with phosphate buffer (pH 4.5) and acetonitrile gradient elution achieves baseline separation of SAX and MET, with validation per ICH guidelines for precision (RSD <2%) and accuracy (98–102%) .

Q. What safety protocols are critical for handling this compound in laboratory settings?

Answer:
this compound poses risks of skin sensitization and respiratory irritation. Key protocols include:

• Personal Protective Equipment (PPE): Nitrile gloves, lab coats, and safety goggles to avoid direct contact .
• Ventilation: Use fume hoods for powder handling to prevent inhalation of dust/particulates .
• Storage: Keep in airtight containers at 2–8°C, away from moisture and incompatible substances (e.g., strong oxidizers) .
• Spill Management: Neutralize spills with inert absorbents (e.g., vermiculite) and dispose of as hazardous waste .

Q. What experimental design considerations are essential for developing controlled-release formulations of this compound?

Answer:
Preformulation studies should focus on:

• Solubility and Stability: Assess pH-dependent solubility (optimal at 4.5–6.5) and photostability under ICH Q1B guidelines .
• Excipient Compatibility: Screen with osmotic agents (e.g., cellulose acetate) and plasticizers (e.g., PEG 400) for bilayer tablets combining immediate-release SAX and controlled-release MET .
• In Vitro Release Testing: Use USP Apparatus II (paddle) at 50 rpm in 0.1N HCl for 2 hours followed by pH 6.8 buffer to simulate gastrointestinal conditions .

Q. How can researchers resolve contradictions between preclinical and clinical pharmacokinetic data for this compound?

Answer:
Discrepancies often arise from species-specific DPP-4 enzyme affinity or metabolite activity. Strategies include:

• Metabolite Profiling: SAX’s active metabolite (M2) contributes 50% of DPP-4 inhibition in humans but exhibits lower potency in rodents .
• Dose Adjustments: Use allometric scaling based on body surface area and enzyme expression levels in target tissues .
• Population Pharmacokinetics: Apply nonlinear mixed-effects modeling (NONMEM) to account for inter-individual variability in clinical trials .

Q. What methodological approaches validate this compound’s selectivity for DPP-4 inhibition over related proteases?

Answer:

• Enzyme Assays: Compare IC₅₀ values against DPP-8 and DPP-9 using fluorogenic substrates (e.g., H-Gly-Pro-AMC). SAX shows >400-fold selectivity for DPP-4 (Ki = 0.6–1.3 nM) .
• Structural Analysis: Molecular docking studies reveal SAX’s cyanopyrrolidine group forms hydrogen bonds with DPP-4’s Glu205 and Tyr547 residues, unlike DPP-8/9 .

Q. What stability challenges arise in this compound formulations, and how are they mitigated?

Answer:

• Hydrolysis: SAX degrades in acidic conditions (e.g., gastric pH). Use enteric coatings (e.g., Eudragit L100) for delayed release .
• Oxidation: Include antioxidants (e.g., ascorbic acid) in lyophilized parenteral formulations to prevent degradation during storage .
• Photodegradation: Protect tablets with opaque packaging (e.g., aluminum blisters) .

Q. How should clinical trials be designed to assess Saxagliptin’s long-term cardiovascular outcomes in type 2 diabetes?

Answer:

• Endpoint Selection: Composite endpoints (e.g., MACE: cardiovascular death, nonfatal MI/stroke) aligned with FDA guidance .
• Comparator Arms: Use active controls (e.g., Sitagliptin) and adjust for baseline HbA1c variability .
• Follow-Up Duration: Minimum 2 years to detect treatment-emergent effects (e.g., heart failure risk) .