Anagliptin (SK-0403)
(Synonyms: 利格列汀; SK-0403) 目录号 : GC31341
A DPP-4 inhibitor
Cas No.:739366-20-2
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Cell experiment: | To evaluate the growth response of cultured smooth muscle cells (SMCs) to s-DPP-4, the bromodeoxyuridine (BrdU) incorporation assay is performed using cell proliferation ELISA kit. Briefly, SMCs are plated at a density of 3000 cells/well in 96-well culture plates with complete media. At 60%-70% confluence, the SMCs are pretreated with or without 1, 10 or 100 μM Anagliptin for 10 minutes and finally stimulated with soluble recombinant human (rh) DPP-4 (5 to 500 ng/mL) for 20 hours. Then, BrdU solution (10 μM) is added to the cells and the cells are cultured for another 4 hours. Then, the cells are dried and fixed, and the cellular DNA is denatured with FixDenat solution for 30 minutes at room temperature. A rat anti-BrdU monoclonal antibody conjugated with peroxidase is added to the culture plates and incubated again at room temperature for 90 minutes. Finally, tetramethylbenzidine is added before incubation for 15 minutes at room temperature. Absorbance is measured by a microplate reader at 370 nm[2]. |
Animal experiment: | Mice[2]Male apoliporotein E (apoE)-deficient mice and C57BL/6 mice at the age of 7 weeks, are housed in specific pathogen-free barrier facilities. Mice are maintained under 12-hour light/dark cycle, and fed a standard rodent diet (22.6% protein, 53.8% carbohydrate, 5.6% fat, 6.6% mineral and vitamin mixture, and 3.3% fiber; total, 356 kcal/100 g) with water ad libitum. At the age of 9 weeks, apoE-deficient mice are fed Anagliptin-containing diet (0.3%, Anagliptin group, n = 30) or DPP-4 inhibitor-free diet (control group n = 30) for 16 weeks[2]. |
References: [1]. Kato N, et al. Discovery and pharmacological characterization of N-[2-({2-[(2S)-2-cyanopyrrolidin-1-yl]-2-oxoethyl}amino)-2-methylpropyl]-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxamide hydrochloride (anagliptin hydrochloride salt) as a potent and selective DPP-IV inhibitor. Bioorg Med Chem. 2011 Dec 1;19(23):7221-7. | |
Anagliptin is an inhibitor of dipeptidyl peptidase 4 (DPP-4; IC50 = 3.8 nM).1 It is selective for DPP-4 over DPP-8 and DPP-9 (IC50s = 68 and 60 nM, respectively). Dietary administration of anagliptin (0.05 and 0.3% w/w) decreases plasma DPP-4 activity, increases plasma GLP-1 levels, suppresses food intake and body weight gain, ameliorates insulin resistance, and improves glucose tolerance in wild-type and glucokinase knockout mouse models of high-fat diet-induced diabetes.2 It decreases hepatic lipid and M1 macrophage accumulation and prevents hepatic fibrosis and steatohepatitis in mice fed a high-cholesterol high-fat diet or a choline-deficient L-amino acid-defined, high-fat (CDAHF) diet.3 Anagliptin also reduces atherosclerotic lesion size in an Apoe-/- mouse model of atherosclerosis.4
1.Kato, N., Oka, M., Murase, T., et al.Discovery and pharmacological characterization of N-[2-({2-[(2S)-2-cyanopyrrolidin-1-yl]-2-oxoethyl}amino)-2-methylpropyl]-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxamide hydrochloride (anagliptin hydrochloride salt) as a potent and selective DPP-IV inhibitorBioorg. Med. Chem.19(23)7221-7227(2011) 2.Nakaya, K., Kubota, N., Takamoto, I., et al.Dipeptidyl peptidase-4 inhibitor anagliptin ameliorates diabetes in mice with haploinsufficiency of glucokinase on a high-fat dietMetabolism62(7)939-951(2013) 3.Sakai, Y., Chen, G., Ni, Y., et al.DPP-4 inhibition with anagliptin reduces lipotoxicity-induced insulin resistance and steatohepatitis in male miceEndocrinology161(10)bqaa139(2020) 4.Ervinna, N., Mita, T., Yasunari, E., et al.Anagliptin, a DPP-4 inhibitor, suppresses proliferation of vascular smooth muscles and monocyte inflammatory reaction and attenuates atherosclerosis in male apo E-deficient miceEndocrinology154(3)1260-1270(2013)
| Cas No. | 739366-20-2 | SDF | |
| 别名 | 利格列汀; SK-0403 | ||
| Canonical SMILES | O=C(C1=CN2C(N=C1)=CC(C)=N2)NCC(C)(NCC(N3[C@H](C#N)CCC3)=O)C | ||
| 分子式 | C19H25N7O2 | 分子量 | 383.45 |
| 溶解度 | DMSO : ≥ 36 mg/mL (93.88 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.6079 mL | 13.0395 mL | 26.079 mL |
| 5 mM | 0.5216 mL | 2.6079 mL | 5.2158 mL |
| 10 mM | 0.2608 mL | 1.304 mL | 2.6079 mL |
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动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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Efficacy and Cardiovascular Safety of DPP-4 Inhibitors
Dipeptidyl peptidase-4 (DPP-4) inhibitors or gliptins belong to the class of incretin mimetics. These drugs have been available on the market for the management of type 2 diabetes mellitus (T2DM) for over a decade. Sitagliptin, linagliptin, vildagliptin, saxagliptin and alogliptin are widely available globally, whilst anagliptin, gemigliptin and teneliptin are used mainly in the Asian countries. The glycemic control conferred by DPP-4 inhibitors varies among individual molecules with an average reduction of glycated hemoglobin (HbA1c) ranging between -0.5 to -1.0% with monotherapy. Additive effects on HbA1c reduction may result from combination therapy with other antidiabetics. Weak evidence from various studies suggests that DPP-4 inhibitors may be useful in treating nonalcoholic fatty liver disease (NAFLD) and polycystic ovary syndrome (PCOS). DPP-4 inhibitors safety is not established in pregnancy, and there is only meagre evidence of its use in T2DM among children. In line with the United States Food and Drug Administration (US FDA) recommendations, sitagliptin, linagliptin, saxagliptin and alogliptin have undergone rigorous cardiovascular outcome trials (CVOTs) in recent years, and the safety data for vildagliptin is available through retrospective analysis of various studies in meta-analysis. Small clinical trial, and meta-analysis based data are available for the CV safety of other DPP-4 inhibitors. In general, the CVOTs and other safety data do not reveal serious warning signals except for saxagliptin (higher risk of hospitalization from heart failure [hHF]), although there is no robust data on the risk of hHF among patients with moderate to severe HF at baseline treated with other DPP-4 inhibitors. This review critically appraises the efficacy and cardiovascular safety of DPP-4 inhibitors to empower clinicians to use this class of antidiabetic medications judiciously.
Comparative review of dipeptidyl peptidase-4 inhibitors and sulphonylureas
Type 2 diabetes (T2DM) is a progressive disease, and pharmacotherapy with a single agent does not generally provide durable glycaemic control over the long term. Sulphonylurea (SU) drugs have a history stretching back over 60 years, and have traditionally been the mainstay choice as second-line agents to be added to metformin once glycaemic control with metformin monotherapy deteriorates; however, they are associated with undesirable side effects, including increased hypoglycaemia risk and weight gain. Dipeptidyl peptidase (DPP)-4 inhibitors are, by comparison, more recent, with the first compound being launched in 2006, but the class now globally encompasses at least 11 different compounds. DPP-4 inhibitors improve glycaemic control with similar efficacy to SUs, but do not usually provoke hypoglycaemia or weight gain, are relatively free from adverse side effects, and have recently been shown not to increase cardiovascular risk in large prospective safety trials. Because of these factors, DPP-4 inhibitors have become an established therapy for T2DM and are increasingly being positioned earlier in treatment algorithms. The present article reviews these two classes of oral antidiabetic drugs (DPP-4 inhibitors and SUs), highlighting differences and similarities between members of the same class, as well as discussing the potential advantages and disadvantages of the two drug classes. While both classes have their merits, the choice of which to use depends on the characteristics of each individual patient; however, for the majority of patients, DPP-4 inhibitors are now the preferred choice.
FABP4 secreted by M1-polarized macrophages promotes synovitis and angiogenesis to exacerbate rheumatoid arthritis
Increasing evidence shows that adipokines play a vital role in the development of rheumatoid arthritis (RA). Fatty acid-binding protein 4 (FABP4), a novel adipokine that regulates inflammation and angiogenesis, has been extensively studied in a variety of organs and diseases. However, the effect of FABP4 on RA remains unclear. Here, we found that FABP4 expression was upregulated in synovial M1-polarized macrophages in RA. The increase in FABP4 promoted synovitis, angiogenesis, and cartilage degradation to exacerbate RA progression in vivo and in vitro, whereas BMS309403 (a FABP4 inhibitor) and anagliptin (dipeptidyl peptidase 4 inhibitor) inhibited FABP4 expression in serum and synovial M1-polarized macrophages in mice to alleviate RA progression. Further studies showed that constitutive activation of mammalian target of rapamycin complex 1 (mTORC1) by TSC1 deletion specifically in the myeloid lineage regulated FABP4 expression in macrophages to exacerbate RA progression in mice. In contrast, inhibition of mTORC1 by ras homolog enriched in brain (Rheb1) disruption specifically in the myeloid lineage reduced FABP4 expression in macrophages to attenuate RA development in mice. Our findings established an essential role of FABP4 that is secreted by M1-polarized macrophages in synovitis, angiogenesis, and cartilage degradation in RA. BMS309403 and anagliptin inhibited FABP4 expression in synovial M1-polarized macrophages to alleviate RA development. Hence, FABP4 may represent a potential target for RA therapy.
Anagliptin promotes apoptosis in mouse colon carcinoma cells via MCT-4/lactate-mediated intracellular acidosis
Cancer cells frequently exhibit an acidic extracellular microenvironment, where inversion of the transmembrane pH gradient is associated with tumor proliferation and metastasis. To elucidate a new therapeutic target against cancer, the current study aimed to determine the mechanism by which the dipeptidyl peptidase-4 inhibitor anagliptin regulates the cellular pH gradient and concomitant extracellular acidosis during cancer progression. A total of 5x105 CT-26 cells (resuspended in phosphate buffer saline) were injected subcutaneously in the right flank of male BALB/c mice (weighing 25-28 g). The tumor samples were harvested, and lactate was detected using a lactate assay kit. Immunohistochemistry was used to detect the Ki67 and PCNA. MTT assay and flow cytometric were used to detect cell viability. Intracellular pH was detected by fluorescence pH indicator. The results revealed that anagliptin effectively reduced tumor growth, but did not affect the body weight of treated mice. Anagliptin reduced the accumulation of lactate in tumor sample. Treatment with anagliptin stimulated the apoptosis of CT-26 cells. And lactate excretion inhibition is accompanied by an increase in extracellular pH (pHe) after treatment with anagliptin. Furthermore, anagliptin induced intracellular acidification and reversed the low pHe gradient via monocarboxylate transporter-4 (MCT-4)-mediated lactate excretion. Additionally, anagliptin reversed the aberrant transmembrane extracellular/intracellular pH gradient by suppressing MCT-4-mediated lactate excretion, while also reducing mitochondrial membrane potential and inducing apoptosis. These data revealed a novel function of anagliptin in regulating lactate excretion from cancer cells, suggesting that anagliptin may be used as a potential treatment for cancer.
Pancreatitis and pancreatic cancer in patientes treated with Dipeptidyl Peptidase-4 inhibitors: An extensive and updated meta-analysis of randomized controlled trials
Aim: Observational studies and metanalyses of randomized trials on Dipeptidyl Peptidase-4 inhibitors (DPP4i) reported discordant results on the risk of pancreatitis and pancreatic cancer with this class of drugs. Aim of the present meta-analysis is the assessment of the effect of DPP4i treatment on the incidence of pancreatitis and pancreatic cancer, collecting all available evidence from randomized controlled trials. Methods Data Sources: an extensive Medline, Embase and Cochrane Database search for sitagliptin or vildagliptin or omarigliptin or saxagliptin or alogliptin or trelagliptin or anagliptin or linagliptin or gemigliptin or evogliptin or teneligliptin was performed up to up to September 30th, 2019. All trials performed on type 2 diabetes, with duration ≥24 weeks, and comparing of DPP4i with placebo or active drugs were collected. The study has been registered on PROSPERO (#153344). Mantel-Haenszel odds ratio (MH-OR) with 95% Confidence Interval (95% CI) was calculated for all outcomes defined above. Results A total of 165 eligible trials were identified. DPP-4 inhibitors were not associated with an increased risk of pancreatitis (MH-OR 1.13 [0.86, 1.47]) or pancreatic cancer (MH-OR 0.86 [0.60, 1.24]) with no significant differences across individual molecules of the class.
Conclusions: available data do not support the hypothesis of an association of DPP4i treatment with pancreatitis. Present data do not suggest any association of DPP4i with pancreatic cancer, although they are insufficient to draw definitive conclusions.