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Anagliptin (formerly known as SK0403) is a novel, potent, orally bioactive, and extremely selective DPP-4 (dipeptidyl peptidase 4) inhibitor with an IC50 of 3.8 nM. It is less selective against DPP-8/9 (IC50 = 68, 60 nM). In Japan, angliptin received approval in 2012 to treat type 2 diabetes mellitus. In clinical trials, these agents not only improved glycemic control but also improved lipid metabolism. In an animal model with high cholesterol, anagliptin had a lipid-lowering effect. This finding implied that the effect was caused by hepatic lipid synthesis being downregulated. Beyond its effects on glucose reduction, anagliptin may also have positive effects on lipid metabolism.
Physicochemical Properties
| Molecular Formula | C19H25N7O2 |
| Molecular Weight | 383.46 |
| Exact Mass | 383.206 |
| Elemental Analysis | C, 59.51; H, 6.57; N, 25.57; O, 8.34 |
| CAS # | 739366-20-2 |
| Related CAS # | Anagliptin hydrochloride;1359670-56-6 |
| PubChem CID | 44513473 |
| Appearance | White to yellow solid powder |
| Density | 1.3±0.1 g/cm3 |
| Index of Refraction | 1.661 |
| LogP | -0.34 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 6 |
| Rotatable Bond Count | 6 |
| Heavy Atom Count | 28 |
| Complexity | 643 |
| Defined Atom Stereocenter Count | 1 |
| SMILES | O=C(C1=CN2C(N=C1)=CC(C)=N2)NCC(C)(NCC(N3[C@H](C#N)CCC3)=O)C |
| InChi Key | LDXYBEHACFJIEL-HNNXBMFYSA-N |
| InChi Code | InChI=1S/C19H25N7O2/c1-13-7-16-21-9-14(11-26(16)24-13)18(28)22-12-19(2,3)23-10-17(27)25-6-4-5-15(25)8-20/h7,9,11,15,23H,4-6,10,12H2,1-3H3,(H,22,28)/t15-/m0/s1 |
| Chemical Name | N-[2-[[2-[(2S)-2-cyanopyrrolidin-1-yl]-2-oxoethyl]amino]-2-methylpropyl]-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxamide |
| Synonyms | SK-0403; SK0403; SK 0403; Brand name: Suiny |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets |
DPP-4 (IC50 = 3.8 nM); DPP-9 (IC50 = 60 nM); DPP-8 (IC50 = 68 nM) Anagliptin (SK-0403) (0-100 μM; 24 h) educes the proliferation of smooth muscle cells induced by s-DPP-4[2]. Anagliptin (100 μM; 10 min) lowers TNF-α production in cultured monocytes[2]. Anagliptin (0.001-10 μM; 24 h) significantly reduces the activity of the protein that binds to sterol regulatory elements in HepG2 cells (21% decrease)[3]. |
| ln Vitro |
Anagliptin (SK-0403) (0-100 μM; 24 h) educes the proliferation of smooth muscle cells induced by s-DPP-4[2]. Anagliptin (100 μM; 10 min) lowers TNF-α production in cultured monocytes[2]. Anagliptin (0.001-10 μM; 24 h) significantly reduces the activity of the protein that binds to sterol regulatory elements in HepG2 cells (21% decrease)[3]. n a sterol regulatory element-binding protein (SREBP) transactivation assay using HepG2 cells, Anagliptin at concentrations of 0.001–10 μmol/L significantly suppressed SREBP promoter activity in a concentration-dependent manner, with a maximum suppression of approximately 21% compared to the control. [3] |
| ln Vivo |
Anagliptin (SK-0403) (0.3%; in diet; 16 weeks) in mice lacking apoliporotein E (apoE) decreases atherosclerotic lesions but does not raise circulating EPC counts[2]. Anagliptin (0.3%; in diet; 4 weeks) shows a lipid-lowering effect in a hyperlipidemic mice model[3]. Administration of Anagliptin (0.3% in diet) for 4 weeks to male low-density lipoprotein receptor (LDLR)-deficient mice significantly reduced plasma total cholesterol levels by 14% and triglyceride levels by 27% compared to the control group. [3] High-performance liquid chromatography analysis revealed that Anagliptin treatment significantly decreased plasma very low-density lipoprotein cholesterol (VLDL-C) and low-density lipoprotein cholesterol (LDL-C) levels, while high-density lipoprotein cholesterol (HDL-C) showed a non-significant decreasing trend. [3] In LDLR-deficient mice, Anagliptin treatment (0.3% in diet for 2 weeks) significantly decreased the hepatic mRNA expression level of SREBP-2 by 15% during the night, while SREBP-1c expression was not significantly altered. [3] DNA microarray analysis of liver samples from Anagliptin-treated mice showed significant associations with pathways related to lipid metabolism, including nuclear receptors in lipid metabolism, fatty acid biosynthesis, and statin pathway. [3] Hepatic de novo triglyceride synthesis tended to be reduced in Anagliptin-treated mice, although the rate of triglyceride secretion in vivo was not altered. [3] |
| Cell Assay |
HepG2 cells were seeded in 96-well plates at 1 × 10⁴ cells per well. The next day, cells were co-transfected with a luciferase reporter vector containing a sterol-responsive element (SRE) promoter (SRE-luc) and a control vector for normalization. Transfection was performed using a commercial transfection reagent. [3] After 24 hours, the medium was replaced with fresh medium containing 5% lipoprotein-deficient serum. Cells were then stimulated with various concentrations of Anagliptin (0.001–10 μmol/L) for 24 hours. [3] Cell lysates were prepared, and luciferase activity was measured using a commercial dual-luciferase assay system according to the manufacturer's instructions. Firefly luciferase activity was normalized to the control luciferase activity. [3] |
| Animal Protocol |
Male apoliporotein E (apoE)-deficient mice[2] 0.3% In diet, 16 weeks Male LDLR-deficient mice at 5 weeks of age were fed a normal chow diet. [3] Starting at 6 weeks of age, mice were administered Anagliptin mixed into their diet at a concentration of 0.3% (w/w) for a period of 4 weeks (for endpoint measurements) or 2 weeks (for night-time sampling). [3] Control mice received the same diet without Anagliptin. [3] Blood samples were collected at the end of the treatment period for analysis of plasma lipids and glucose. For night-time gene expression analysis, samples were collected between 22:00 and 02:00 hours. [3] Under these conditions, the plasma concentration of Anagliptin was approximately 600 ng/mL, resulting in approximately 80% inhibition of plasma DPP-4 activity. [3] |
| ADME/Pharmacokinetics |
In LDLR-deficient mice fed a diet containing 0.3% Anagliptin, the achieved plasma concentration was approximately 600 ng/mL. [3] This plasma concentration was associated with approximately 80% inhibition of DPP-4 activity. [3] |
| References |
[1]. 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. [2]. Anagliptin, a DPP-4 inhibitor, suppresses proliferation of vascular smooth muscles and monocyte inflammatory reaction and attenuates atherosclerosis in male apo E-deficient mice. Endocrinology. 2013 Mar;154(3):1260-70. [3]. Mechanism of lipid-lowering action of the dipeptidyl peptidase-4 inhibitor, anagliptin, in low-density lipoprotein receptor-deficient mice. J Diabetes Investig. 2017 Mar;8(2):155-160. |
| Additional Infomation |
Anagliptin is an amino acid amide. Anagliptin is under investigation for the treatment of LDL Cholesterol, Coronary Disease, Diabetes Mellitus, Glycosylated Hemoglobin, and Dipeptidyl-Peptidase 4 Inhibitors. Anagliptin is an orally available, potent, selective inhibitor of dipeptidyl peptidase 4 (DPP-4), with hypoglycemic activity. Compared to vildagliptin, anagliptin caused longer lasting inhibition of DPP-4 activity. Anagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor used for the treatment of type 2 diabetes. [3] Beyond its glucose-lowering effect, clinical trials and this preclinical study suggest that Anagliptin has beneficial effects on lipid metabolism, reducing plasma total cholesterol, LDL-C, and triglyceride levels. [3] The proposed mechanism for its lipid-lowering action involves the downregulation of hepatic sterol regulatory element-binding protein-2 (SREBP-2) expression and activity, leading to reduced hepatic lipid synthesis. [3] The study used LDLR-deficient mice as a normoglycemic hyperlipidemic model to isolate the lipid effects from glucose-lowering effects. [3] |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.52 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (6.52 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6078 mL | 13.0392 mL | 26.0783 mL | |
| 5 mM | 0.5216 mL | 2.6078 mL | 5.2157 mL | |
| 10 mM | 0.2608 mL | 1.3039 mL | 2.6078 mL |