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DPP-4 inhibitor 1 Sale

目录号 : GC31512

DPP-4inhibitor1(compound5)是有效的、长效的二肽基肽酶-4(DPP-4)的抑制剂,有治疗2型糖尿病的潜力,其KD值为0.177nM。

DPP-4 inhibitor 1 Chemical Structure

Cas No.:1915007-89-4

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产品描述

DPP-4 inhibitor 1 (compound 5) is a potent and long acting Dipeptidyl peptidase-4 (DPP-4) inhibitor for t treatment of T2DM, with a KD of 0.177 nM[1].

A single-dose oral administration of DPP-4 inhibitor 1 (compound 5) (3 mg/kg) inhibits >80% of DPP-4 activity for more than 7 days in diabetic mice[1].Administration of DPP-4 inhibitor 1 (compound 5) (3 and 10 mg/kg, p.o., qw for 8 weeks) causes significant reductions in fasting blood glucose (FBG) levels, and the average reduction during the entire treatment period is 24.7 and 33.1%, respectively. Chronic administration of DPP-4 inhibitor 1 (compound 5) (10 mg/kg/week) also significantly improves the glucose tolerance of the diabetic mice[1].|| Animal Model:|ICR mice[1].|Dosage:|0.3, 3, 10 mg/kg.|Administration:|Oral, once.|Result:|Resulted in a time- and dose-dependent inhibition of plasma DPP-4 activity.The active GLP-1 and insulin level were significantly increased compared with the vehicle control.|| Animal Model:|Genetic-type 2 diabetes animal models in db/db Mice[1].|Dosage:|3 and 10 mg/kg.|Administration:|Oral administration once a week, for 8 weeks.|Result:|Caused significant reductions in fasting blood glucose (FBG) levels.Improved the glucose tolerance of the diabetic mice significantly.

[1]. Li S, et al. Discovery of a Natural-Product-Derived Preclinical Candidate for Once-Weekly Treatment of Type 2 Diabetes. J Med Chem. 2019 Feb 1.

Chemical Properties

Cas No. 1915007-89-4 SDF
Canonical SMILES FC1=CC(F)=C([C@H]2OC3=CC=C(C=C(C#N)C(OC)=C4)C4=C3C[C@@H]2N)C=C1F
分子式 C21H15F3N2O2 分子量 384.35
溶解度 Soluble in DMSO 储存条件 Store at -20°C
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1 mM 2.6018 mL 13.009 mL 26.018 mL
5 mM 0.5204 mL 2.6018 mL 5.2036 mL
10 mM 0.2602 mL 1.3009 mL 2.6018 mL
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Research Update

SGLT2 inhibitor plus DPP-4 inhibitor as combination therapy for type 2 diabetes: A systematic review and meta-analysis

To assess the efficacy and safety of sodium-glucose co-transporter 2 (SGLT2) inhibitors plus a dipeptidyl peptidase-4 (DPP-4) inhibitor in patients with type 2 diabetes mellitus (T2DM), we performed a systematic review and meta-analysis of 14 randomized controlled trials (RCTs) involving 4828 patients. Compared with a DPP-4 inhibitor, SGLT2 inhibitor/DPP-4 inhibitor combination therapy was significantly associated with a decrease in glycaemic control (HbA1c, -0.71%; fasting plasma glucose [FPG], -25.62 mg/dL; postprandial plasma glucose, -44.00 mg/dL), body weight (-2.05 kg) and systolic blood pressure (-5.90 mm Hg), but an increase in total cholesterol (TC) of 3.24%, high-density lipoprotein of 6.15% and low-density lipoprotein of 2.55%. Adding a DPP-4 inhibitor to an SGLT2 inhibitor could reduce HbA1c by -0.31%, FPG by -8.94 mg/dL, TC by -1.48% and triglycerides by -3.25%. Interestingly, low doses of an SGLT2 inhibitor in the combination has similar or even better efficacy in some aspects than high doses. Similar adverse events were observed for the combination therapy, with the exception of genital infection vs DPP-4 inhibitor (risk ratio [RR], 5.31) and consistent genital infection vs an SGLT2 inhibitor (RR, 0.61). Further studies are warranted to confirm these results.

DPP-4 Inhibitor Linagliptin Ameliorates Oxidized LDL-Induced THP-1 Macrophage Foam Cell Formation and Inflammation

Introduction: Atherosclerosis is one of the major causes of cardiovascular diseases. Lipid uptake and accumulation in macrophages play a major role in atherosclerotic plaque formation from its initiation to advanced atheroma formation. The dipeptidyl peptidase-4 (DPP-4) inhibitor Linagliptin is commonly used to lower blood glucose in type 2 diabetes patients. Recent studies report that Linagliptin has cardiovascular protective and anti-inflammatory effects.
Methods: THP-1 macrophage cells were treated with 100 nM PMA for 72 hour to induce foam cell formation. The differentiated cells were exposed to 100 μg/mL ox-LDL in the presence or absence of the DPP-4 inhibitor Linagliptin. The expression levels of DPP-4 and inflammatory cytokines were detected by RT-PCR, ELISA, and Western blot experiments. The cellular ROS level was measured by staining the cells with the fluorescent probe DCFH-DA. The separation of lipoprotein fractions was achieved by high-performance liquid chromatography (HPLC). The cells were labeled with fluorescent-labeled cholesterol to measure cholesterol efflux, and lipid droplets were revealed by Nile red staining.
Results: The presence of Linagliptin significantly reduced ox-LDL-induced cytokine production (IL-1β and IL-6) and ROS production. Linagliptin ameliorated ox-LDL-induced lipid accumulation and impaired cholesterol efflux in macrophages. Mechanistically, this study showed that Linagliptin mitigated ox-LDL-induced expression of the scavenger receptors CD36 and LOX-1, but not SRA. Furthermore, Linagliptin increased the expression of the cholesterol transporter ABCG1, but not ABCA1.
Conclusion: Linagliptin possesses a potent inhibitory effect on THP-1 macrophage-derived foam cell formation in response to ox-LDL. This effect could be mediated through a decrease in the expression of CD36 and LOX-1 on macrophages and an increase in the expression of the cholesterol transporter ABCG1. This study indicates that the DPP-4 inhibitor Linagliptin plays a critical role in preventing foam cell formation in vitro. However, future research using an atherosclerotic animal model is necessary to determine its effectiveness and to prove its potential implication in the prevention and treatment of atherosclerosis.

[DPP-4 inhibitor]

Now seven compounds of DPP-4 inhibitor are available in Japan. They can be used in any stage of type 2 diabetes if the insulin secretion capacity is retained; first-line choice to third-line choice or combination with insulin therapy. There is no apparent difference in effect of each DPP-4 inhibitor on glycemic control; HbA1c levels are decreased by 0.6- 1.0% by monotherapy. Generally the drug is more effective for improving glycemic control in Japanese population compared to that in Western population. In addition, basal insulin therapy could be switched to the combination therapy with DPP-4 inhibitor and sulfonyl- urea in Japanese type 2 diabetes in cases where insulin secretion capacity is sufficiently preserved. Here we summarize the effect of DPP-4 inhibitor on glycemic control and algorithm for DPP-4 inhibitor treatment.

DPP-4 Inhibitors and Increased Reporting Odds of Bullous Pemphigoid: A Pharmacovigilance Study of the FDA Adverse Event Reporting System (FAERS) from 2006 to 2020

Background: In recent years, an association between dipeptidyl peptidase-4 (DPP-4) inhibitors and bullous pemphigoid has been detected in pharmacovigilance studies in European and Asian countries; however, no pharmacovigilance data have been published yet in the USA.
Objective: The objective of this study was to examine the relationship between bullous pemphigoid and DPP-4 inhibitors and other oral diabetes mellitus medications in the FDA Adverse Event Reporting System (FAERS).
Methods: Case/non-case analyses were performed in the FAERS using data from 2006 to 2020 to examine the reporting odds ratio (ROR) signal for bullous pemphigoid for all classes of oral diabetes medications. These analyses were performed under multiple conditions to control for bias: (1) comparison to all other drugs in the FAERS; (2) comparison to other diabetes medications; and (3) comparison to all other diabetes medications where only a single agent was implicated.
Results: A statistically significant ROR for bullous pemphigoid was found for DPP-4 inhibitors under all conditions: (1) 109.79 (95% confidence interval [CI] 101.61-118.62); (2) 74.46 (95% CI 60.58-91.52); and (3) 35.94 (95% CI 27.91-46.28). A larger signal was seen for non-US Food and Drug Administration (FDA)-approved (anagliptin, vildagliptin, teneligliptin) vs FDA-approved DPP-4 inhibitors (alogliptin, linagliptin, saxagliptin, sitagliptin), likely because of an overestimation of the ROR for non-FDA-approved drugs. The largest signal was seen under conditions 1 and 2 with vildagliptin (1) 1022.83 (95% CI 909.45-1150.35) and (2) 158.84 (95% CI 127.01-198.66) followed by anagliptin (1) 628.63 (95% CI 221.36-1785.24) and (2) 60.64 (95% CI 20.98-175.26), alogliptin, teneligliptin, linagliptin, sitagliptin, and saxagliptin. Under condition 3, the largest signal was seen with linagliptin 122.25 (95% CI 93.96-159.07). Both metformin and the sulfonylureas had a significant ROR under condition 2 [3.42 (95% CI 3.01-3.89) and 2.07 (95% CI 1.66-2.57) respectively]; however, this association was not present under condition 3 as only confounded cases occurred, and a large majority of reported cases had concurrent exposure to a DPP-4 inhibitor.
Conclusions: Our findings support an association between DPP-4 inhibitors and bullous pemphigoid. This association was maintained under controls to limit bias and falsely elevated signal, including controlling for disease state and cases with multiple drug exposures. Non-FDA-approved DPP-4 inhibitors had a larger ROR compared with FDA-approved DPP-4 inhibitors, likely owing to fewer reported adverse effects overall for non-FDA-approved drugs in FAERS.

[Once-weekly DPP-4 inhibitor]

Trelagliptin is the first once-weekly dipeptidyl peptidase-4(DPP-4) inhibitor in the world. Trelagliptin inhibits DPP-4 activity with lower drug concentration compared with other once- (or twice-) daily DPP-4 inhibitors in in vitro study. More than 70 % of DPP-4 activity is inhibited even 1 week after administration of trelagliptin administration in human study. 24-week trelagliptin monotherapy improved HbA1c(-0.33%) and fasting plasma glucose levels in Japanese patients with type 2 diabetes. Trelagliptin did not affect body weight and frequency of hypoglycemic events in this study. 52-week monotherapy and add-on therapy of trelagliptin also improved HbA1c levels without body weight gain and severe hypoglycemia. Therefore, trelagliptin has high efficacy and safety on glucose control in Japanese patients with type 2 diabetes.