Alogliptin

合成路线和反应条件

阿罗格列汀是通过多步合成过程合成的，涉及关键中间体的形成。合成路线通常从制备 2-({6-[(3R)-3-氨基哌啶-1-基]-3-甲基-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基}甲基)苯腈开始。 然后，该中间体经受各种化学反应，包括胺化和环化，以产生最终产物 .

工业生产方法

在工业环境中，阿罗格列汀的生产涉及使用高效液相色谱 (HPLC) 进行纯化和质量控制。该过程经过优化，以确保最终产物的产率高且纯度高。 在阿罗格列汀的工业生产中，通常使用先进的分析技术，如反相高效液相色谱 (RP-HPLC) .

反应类型

阿罗格列汀会经历各种化学反应，包括：

氧化： 阿罗格列汀在特定条件下可以被氧化形成相应的氧化物。

还原： 还原反应可用于修饰阿罗格列汀中的官能团。

取代： 阿罗格列汀可以发生取代反应，其中特定的原子或基团被其他原子或基团取代

常用试剂和条件

阿罗格列汀化学反应中常用的试剂包括：

氧化剂： 例如过氧化氢和高锰酸钾。

还原剂： 例如硼氢化钠和氢化铝锂。

取代试剂： 例如卤素和烷基化试剂

主要形成的产物

阿罗格列汀化学反应形成的主要产物取决于所用反应条件和试剂。 例如，氧化可能会产生氧化物，而取代反应可能会产生卤代或烷基化衍生物 .

Management of Type 2 Diabetes Mellitus

Alogliptin is primarily indicated for improving glycemic control in adults with type 2 diabetes. It is often prescribed as monotherapy or in combination with other antidiabetic medications such as metformin or pioglitazone. Clinical trials have demonstrated that this compound effectively reduces hemoglobin A1c (HbA1c) levels, with studies showing a significant reduction of approximately 0.58% compared to placebo after 16 weeks .

Cardiovascular Safety and Outcomes

The EXAMINE trial evaluated the cardiovascular safety of this compound in patients with a recent acute coronary syndrome. Results indicated that this compound did not increase the risk of major adverse cardiovascular events compared to placebo, making it a viable option for diabetic patients with cardiovascular concerns . Additionally, long-term studies suggest that early initiation of this compound may prevent the progression of atherosclerosis in diabetic patients without prior cardiovascular disease .

Potential Renal Benefits

Research indicates that this compound may have protective effects on renal function in patients with type 2 diabetes. The drug has been associated with a lower incidence of renal impairment compared to other antidiabetic agents, suggesting its utility in managing diabetes-related kidney complications .

Efficacy and Safety Data

This compound has been shown to be effective in reducing fasting plasma glucose levels and achieving target HbA1c levels without causing significant weight gain or hypoglycemia, which are common concerns with other diabetes medications . The most frequent side effects reported include headaches, gastrointestinal disturbances, and skin rashes .

Case Study: Long-term Efficacy

In a cohort study involving 341 subjects, early initiation of this compound was linked to improved long-term cardiovascular outcomes without increasing cancer risk. This study highlights the potential for this compound not only to manage diabetes but also to contribute positively to overall patient health outcomes over extended periods .

Research Findings

• SPEAD-A Trial: This trial demonstrated that this compound significantly attenuated the progression of carotid atherosclerosis over two years, reinforcing its role in cardiovascular protection for diabetic patients .
• Phase 3 Trials: Multiple phase 3 trials have confirmed the efficacy and safety profile of this compound across diverse populations, including Asian cohorts, showing consistent results in HbA1c reduction and tolerability .

阿罗格列汀通过抑制 DPP-4 酶发挥作用，该酶负责降解增血糖素激素。通过抑制 DPP-4，阿罗格列汀提高了活性增血糖素激素的水平，例如 GLP-1 和 GIP。这些激素增强胰腺β细胞的胰岛素分泌，并减少胰腺α细胞的胰高血糖素分泌，从而改善血糖控制。 阿罗格列汀抑制 DPP-4 也会导致活性增血糖素水平延长，这有助于其治疗效果 .

阿罗格列汀是 DPP-4 抑制剂类的一部分，其中包括其他类似化合物，例如：

• 西格列汀
• 沙格列汀
• 利格列汀
• 维格列汀

阿罗格列汀的独特性

阿罗格列汀在 DPP-4 抑制剂中是独一无二的，因为它具有高度选择性和口服生物利用度。它具有相对较长的半衰期，允许每天一次给药。 此外，阿罗格列汀已被证明具有良好的安全性，低血糖风险低，对体重的影响最小 .

Alogliptin is a selective dipeptidyl peptidase-4 (DPP-4) inhibitor utilized primarily in the management of type 2 diabetes mellitus (T2DM). Its mechanism of action involves the inhibition of DPP-4, an enzyme responsible for the degradation of incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). By inhibiting DPP-4, this compound increases the levels of these hormones, leading to enhanced insulin secretion and improved glycemic control.

Pharmacokinetics and Pharmacodynamics

Absorption and Distribution:
this compound exhibits high bioavailability with a median time to peak concentration (Tmax) ranging from 1 to 2 hours and a half-life of approximately 12.4 to 21.4 hours. It is well-distributed in tissues, with a mean volume of distribution of 60.9 L, indicating extensive tissue penetration .

DPP-4 Inhibition:
Clinical studies show that this compound achieves significant DPP-4 inhibition, with mean plasma DPP-4 activity reduced by over 80% after 24 hours following administration. The inhibition rates after single doses range from 74.3% to 94% at 24 hours, and up to 99% after multiple doses over a period of 14 days .

Clinical Efficacy

This compound has been evaluated in various clinical trials for its efficacy in lowering hemoglobin A1c (HbA1c) levels and fasting plasma glucose (FPG).

Case Study Results

In a Phase 3 trial conducted across China, Taiwan, and Hong Kong, this compound significantly reduced HbA1c levels compared to placebo when used alone or in combination with other antidiabetic agents . The results indicated that patients receiving this compound were more likely to achieve target HbA1c levels of ≤6.5% or ≤7.0% compared to those on placebo.

Safety Profile

This compound is generally well-tolerated, with few adverse effects reported. The most common side effects include mild gastrointestinal disturbances and skin reactions such as pruritus. Importantly, no significant weight gain has been associated with its use, making it a favorable option for patients concerned about weight management .

Impact on Beta-cell Function

Research indicates that this compound may have a protective effect on pancreatic beta-cell function. However, studies have shown mixed results regarding its ability to improve beta-cell function metrics such as the proinsulin:insulin ratio and HOMA-β scores. While some studies suggest potential benefits, long-term data are required to confirm these findings .

Basic Research Questions

Q. What experimental methodologies are recommended for validating the stability-indicating properties of analytical methods for Alogliptin in combination therapies?

• Use ion-pair reverse-phase high-performance liquid chromatography (RP-HPLC) with experimental design (e.g., factorial design) to optimize robustness and accuracy. For example, Mahrouse & Lamie (2019) validated a method for simultaneous quantification of this compound, Metformin, and Repaglinide using Design of Experiments (DoE) to assess factors like pH, buffer concentration, and column temperature . Accuracy was confirmed via spike-recovery tests (80–120% concentration ranges), with % recovery within 98–102% .

Q. How do pharmacokinetic (PK) and pharmacodynamic (PD) profiles of this compound differ between pediatric and adult populations with type 2 diabetes mellitus (T2DM)?

• A randomized open-label study compared single-dose PK/PD in children (12.5 mg), adolescents (25 mg), and adults (25 mg). This compound’s median T_max (2–4 h) and DPP-4 inhibition (>80% at peak) were consistent across groups. However, adolescents exhibited 24% lower steady-state C_max and 11% lower AUC_0-tau vs. adults, necessitating dose adjustments for pediatric cohorts .

Q. What evidence supports this compound’s cardiovascular safety in high-risk T2DM patients post-acute coronary syndrome (ACS)?

• The EXAMINE trial (n=5,380) demonstrated non-inferiority of this compound vs. placebo for major adverse cardiovascular events (MACE; HR=0.96, 95% CI upper boundary=1.16) over 18 months. Subgroup analysis of patients on metformin + sulfonylurea (n=1,398) showed no increased risk of hypoglycemia or pancreatitis .

Q. How does this compound’s efficacy as monotherapy compare to traditional therapies like sulfonylureas in Japanese T2DM patients?

• A 12-week dose-ranging trial (n=480) found this compound (6.25–50 mg/day) reduced HbA1c by 0.54–0.87% vs. placebo (p<0.001), with sustained efficacy over 52 weeks. Unlike sulfonylureas, this compound showed no dose-dependent weight gain or severe hypoglycemia .

Advanced Research Questions

Q. How can researchers address heterogeneity in meta-analyses of this compound’s dose-response relationships?

• Use hierarchical Bayesian models to account for covariates like renal function, age, and drug-drug interactions. A meta-analysis of this compound’s PD data highlighted limitations in existing studies due to unadjusted confounders (e.g., comorbidities, baseline HbA1c). Sensitivity analyses and subgroup stratification are critical to mitigate bias .

Q. What structural modifications enhance this compound’s DPP-4 inhibitory activity?

• Structure-activity relationship (SAR) studies identified multi-substituted pyridone scaffolds as key. For example, compound 11a (IC₅₀=3.2 nM) outperformed this compound (IC₅₀=5.0 nM) by replacing the quinazolinone core with pyridone and optimizing hydrophobic interactions via fluorophenyl groups .

Q. What methodological challenges arise in post hoc analyses of this compound’s long-term safety in triple therapy (e.g., metformin + sulfonylurea + this compound)?

• The EXAMINE trial’s post hoc analysis (n=1,398) faced confounding from variable adherence to background therapies. Propensity score matching and time-dependent Cox models were used to adjust for imbalances in baseline HbA1c and renal function .

Q. How can sustained-release formulations of this compound improve patient adherence and glycemic control?

• A 2³ factorial design optimized injectable PLGA-based in situ gel implants (ISGI). NMP/DMSO solvents reduced burst release (<15% at 24 h) and extended therapeutic exposure (>14 days). In diabetic rats, a single ISGI dose maintained glucose-lowering effects comparable to daily oral dosing .

Q. Methodological Recommendations

• For PK/PD modeling : Integrate sparse sampling protocols (e.g., 0–72 h post-dose) with nonlinear mixed-effects models (NONMEM) to account for inter-individual variability .
• For clinical trial design : Use adaptive non-inferiority margins (e.g., HR<1.3 for MACE) and pre-specified subgroup analyses to enhance statistical rigor .
• For analytical validation : Apply DoE and robustness testing (e.g., Taguchi models) to optimize chromatographic conditions and minimize variability .