 Chemical Structure.png)
Physicochemical Properties
| Molecular Formula | C38H52CAN2O8 |
| Molecular Weight | 704.9061 |
| Exact Mass | 704.334 |
| CAS # | 207844-01-7 |
| Related CAS # | Mitiglinide calcium;145525-41-3;Mitiglinide;145375-43-5;Mitiglinide-d8 calcium hydrate |
| PubChem CID | 6918235 |
| Appearance | Typically exists as solid at room temperature |
| Melting Point | 179-185ºC |
| LogP | 5.53 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 8 |
| Rotatable Bond Count | 8 |
| Heavy Atom Count | 49 |
| Complexity | 411 |
| Defined Atom Stereocenter Count | 6 |
| SMILES | [Ca+2].O=C(C([H])([H])[C@@]([H])(C(=O)[O-])C([H])([H])C1C([H])=C([H])C([H])=C([H])C=1[H])N1C([H])([H])[C@]2([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[C@]2([H])C1([H])[H].O=C(C([H])([H])[C@@]([H])(C(=O)[O-])C([H])([H])C1C([H])=C([H])C([H])=C([H])C=1[H])N1C([H])([H])[C@@]2([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[C@@]2([H])C1([H])[H].O([H])[H].O([H])[H] |
| InChi Key | QEVLNUAVAONTEW-UZYHXJQGSA-L |
| InChi Code | InChI=1S/2C19H25NO3.Ca.2H2O/c2*21-18(20-12-15-8-4-5-9-16(15)13-20)11-17(19(22)23)10-14-6-2-1-3-7-14;;;/h2*1-3,6-7,15-17H,4-5,8-13H2,(H,22,23);;2*1H2/q;;+2;;/p-2/t2*15-,16+,17-;;;/m00.../s1 |
| Chemical Name | calcium;(2S)-4-[(3aS,7aR)-1,3,3a,4,5,6,7,7a-octahydroisoindol-2-yl]-2-benzyl-4-oxobutanoate;dihydrate |
| 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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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 |
Mitiglinide calcium hydrate (KAD1229) targets ATP-sensitive K+ (KATP) channels in pancreatic β-cells (IC50 ≈ 0.4 μM for channel inhibition; EC50 ≈ 0.1 μM for insulin secretion stimulation) [1] |
| ln Vitro |
Mitiglinide calcium hydrate does not significantly inhibit Kir6.2/SUR2A or Kir6.2/, even at high doses. However, it does inhibit Kir6.2/SUR1 channel currents in a dose-dependent manner (IC50 value, 100 nM). SUR2B channel current (less than 10 μM in a greater number of COS-1 cells) [1]. - Isolated pancreatic islets were treated with Mitiglinide calcium hydrate (KAD1229) at concentrations ranging from 0.01 to 10 μM. The drug stimulated insulin secretion in a dose-dependent manner, with significant secretion enhancement observed at concentrations ≥0.1 μM. At 1 μM, insulin secretion was increased by approximately 2.3-fold compared to the control group [1] - Using patch-clamp technique, Mitiglinide calcium hydrate (KAD1229) was shown to inhibit KATP channel currents in pancreatic β-cells. The inhibition was rapid and reversible, with a half-maximal inhibitory concentration (IC50) of ~0.4 μM. This inhibition was comparable to that of nateglinide (IC50 ≈ 0.3 μM) but more potent than glibenclamide (IC50 ≈ 0.8 μM) at the tested concentrations [1] - In isolated pancreatic β-cells, Mitiglinide calcium hydrate (KAD1229) induced a concentration-dependent increase in intracellular Ca2+ concentration, which was blocked by KATP channel openers, confirming that Ca2+ influx was mediated via KATP channel closure [1] |
| ln Vivo |
The increase in plasma glucose levels following a meal and the rise in the area under the curve of plasma glucose levels (AUC glucose) within five hours following a meal are both inhibited by mitiglide calcium hydrate (1-3 mg/kg; oral) [2]. - In type 2 diabetic rats (induced by high-fat diet plus low-dose streptozotocin), oral administration of Mitiglinide calcium hydrate (KAD1229) at doses of 1, 3, and 10 mg/kg significantly reduced postprandial plasma glucose levels. At 3 mg/kg, the peak glucose level at 60 minutes after meal load was decreased by ~42% compared to the vehicle-treated group, and the glucose-lowering effect persisted for up to 120 minutes [2] - The glucose-lowering efficacy of Mitiglinide calcium hydrate (KAD1229) at 10 mg/kg was comparable to that of nateglinide (10 mg/kg) and glibenclamide (0.3 mg/kg) in the same diabetic rat model. However, Mitiglinide calcium hydrate (KAD1229) showed a faster onset of action (significant glucose reduction observed at 30 minutes post-administration) compared to glibenclamide [2] - In normal rats, Mitiglinide calcium hydrate (KAD1229) at doses up to 30 mg/kg did not cause significant hypoglycemia (plasma glucose levels remained above 70 mg/dL), whereas glibenclamide (1 mg/kg) induced mild hypoglycemia in 30% of the animals [2] |
| Enzyme Assay |
- Pancreatic β-cells were dissociated from rat pancreatic islets and placed in a recording chamber. Patch-clamp electrodes filled with intracellular solution were used to form whole-cell configurations. KATP channel currents were recorded under voltage-clamp conditions (holding potential of -70 mV) before and after application of Mitiglinide calcium hydrate (KAD1229) at various concentrations. Current amplitudes were measured, and concentration-response curves were constructed to calculate IC50 values. The specificity of the inhibition was confirmed by co-application of a KATP channel opener, which reversed the inhibitory effect of the drug [1] |
| Cell Assay |
- Pancreatic islets were isolated from rats via collagenase digestion and purified by density gradient centrifugation. Islets were cultured overnight in RPMI 1640 medium supplemented with fetal bovine serum. For insulin secretion assays, islets were preincubated in Krebs-Ringer bicarbonate buffer (KRBB) for 1 hour, then treated with Mitiglinide calcium hydrate (KAD1229) at different concentrations in KRBB containing 11 mM glucose. After 1 hour of incubation, the supernatant was collected, and insulin concentrations were measured using a radioimmunoassay. For intracellular Ca2+ measurement, islets were loaded with a Ca2+-sensitive fluorescent dye, and fluorescence intensity was monitored using a confocal microscope during drug treatment [1] |
| Animal Protocol |
Animal/Disease Models: Pregnant Wistar rats (12 weeks) [2] Doses: 0.3 mg/kg, 1 mg/kg, 3 mg/kg Route of Administration: Oral Experimental Results: Dose-dependent inhibition of AUC glucose levels. - Type 2 diabetic rats were prepared by feeding a high-fat diet for 4 weeks followed by a single intraperitoneal injection of streptozotocin (30 mg/kg). Rats with fasting plasma glucose levels ≥13.9 mmol/L and postprandial glucose levels ≥16.7 mmol/L were selected for the study. Mitiglinide calcium hydrate (KAD1229) was dissolved in 0.5% carboxymethylcellulose sodium solution to prepare formulations of different concentrations. The drug was administered orally to rats 30 minutes before a standard meal load (2 g/kg body weight of glucose). Blood samples were collected from the tail vein at 0, 30, 60, 90, and 120 minutes after the meal, and plasma glucose levels were measured using a glucose oxidase method. For comparison, separate groups of rats were treated with nateglinide, glibenclamide, or vehicle alone [2] - Normal Sprague-Dawley rats were used to evaluate the risk of hypoglycemia. Mitiglinide calcium hydrate (KAD1229) was administered orally at doses of 10, 20, and 30 mg/kg, and plasma glucose levels were measured at 0, 1, 2, 4, and 6 hours post-administration. Rats were fasted for 12 hours before drug administration [2] |
| References |
[1]. Y Sunaga, et al. The effects of mitiglinide (KAD-1229), a new anti-diabetic drug, on ATP-sensitive K+ channels and insulin secretion: comparison with the sulfonylureas and nateglinide. Eur J Pharmacol. 2001 Nov 9;431(1):119-25. [2]. Kiyoshi Ichikawa, et al. Effect of KAD-1229, a novel hypoglycaemic agent, on plasma glucose levels after meal load in type 2 diabetic rats. Clin Exp Pharmacol Physiol. May-Jun 2002;29(5-6):423-7. |
| Additional Infomation |
See also: Mitiglinide (annotation moved to). - Mitiglinide calcium hydrate (KAD1229) exerts its hypoglycemic effect by closing KATP channels in pancreatic β-cells, which leads to membrane depolarization, opening of voltage-dependent Ca2+ channels, Ca2+ influx, and subsequent insulin secretion [1] - Compared to sulfonylureas (e.g., glibenclamide), Mitiglinide calcium hydrate (KAD1229) has a shorter duration of action and lower risk of hypoglycemia, making it suitable for postprandial glucose control in type 2 diabetes [1][2] - The binding site of Mitiglinide calcium hydrate (KAD1229) on KATP channels is distinct from that of sulfonylureas, as indicated by competitive binding experiments showing no cross-competition between the drug and glibenclamide [1] |
Solubility Data
| Solubility (In Vitro) |
DMSO : ~25 mg/mL (~70.93 mM) H2O : < 0.1 mg/mL |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (7.09 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 (7.09 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 | 1.4186 mL | 7.0931 mL | 14.1862 mL | |
| 5 mM | 0.2837 mL | 1.4186 mL | 2.8372 mL | |
| 10 mM | 0.1419 mL | 0.7093 mL | 1.4186 mL |