 Chemical Structure.png)
Gliclazide (S-1702; trade names Diamicron among others), a sulfonylurea insulin secretagogue, is an approved medication for the treatment of type 2 diabetes. It acts as a potent and ATP-sensitive potassium currents blocker with an IC50 of 184 nM, and can stimulate β cells of the pancreas to release insulin.
Physicochemical Properties
| Molecular Formula | C15H21N3O3S | |
| Molecular Weight | 323.41 | |
| Exact Mass | 323.13 | |
| CAS # | 21187-98-4 | |
| Related CAS # | Gliclazide-d4;1185039-30-8 | |
| PubChem CID | 3475 | |
| Appearance | White to off-white solid powder | |
| Density | 1.4±0.1 g/cm3 | |
| Melting Point | 163-169 °C(lit.) | |
| Index of Refraction | 1.624 | |
| LogP | 1.57 | |
| Hydrogen Bond Donor Count | 2 | |
| Hydrogen Bond Acceptor Count | 4 | |
| Rotatable Bond Count | 3 | |
| Heavy Atom Count | 22 | |
| Complexity | 497 | |
| Defined Atom Stereocenter Count | 0 | |
| InChi Key | BOVGTQGAOIONJV-UHFFFAOYSA-N | |
| InChi Code | InChI=1S/C15H21N3O3S/c1-11-5-7-14(8-6-11)22(20,21)17-15(19)16-18-9-12-3-2-4-13(12)10-18/h5-8,12-13H,2-4,9-10H2,1H3,(H2,16,17,19) | |
| Chemical Name | 1-(3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl)-3-(4-methylphenyl)sulfonylurea | |
| Synonyms |
|
|
| 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 |
ATP-sensitive potassium channels (KATP channels) in mouse pancreatic beta cells: IC₅₀ = 0.1 μM; no significant inhibitory activity against KATP channels in rat cardiac myocytes or arterial smooth muscle cells (IC₅₀ > 100 μM) [2] |
||
| ln Vitro |
Gliclazide (S1702) further explains the mechanism underlying its hypoglycemic effect: the drug's insulinotropic sulfonylurea effect is further enhanced by the observed improvements in GLUT4 translocation and insulin sensitivity, which counteract the insulin resistance that hydrogen peroxide causes in 3T3L1 adipocytes [1]. Gliclazide demonstrated a significant reduction in efficacy in cardiac and smooth muscle, with IC50s of 19.5 +/- 5.4 micromol/l (n = 6–12) and 37.9 +/– 1.0 micromol/l (n = 5–10), respectively. However, it was significantly more effective in blocking whole-cell beta-cell KATP currents in this latter tissue. The drug affected whole-cell KATP currents in all three tissues, but its effects were quickly reversible. Gliclazide (1 micromol/l) on beta-cells led to a maximum of 66 +/- 13% inhibition (n=5) in inside-out patches, while over 98% block was produced in the whole-cell configuration. is a high-potency sulphonylurea that exhibits over heart and smooth muscle specificity for the pancreatic beta-cell KATP channel. It stands apart from glibenclamide in this regard[2]. 1. In differentiated 3T3L1 adipocytes induced to insulin resistance by hydrogen peroxide (H₂O₂, 200 μM for 2 hours), treatment with Gliclazide (S1702; Diamicron) (10 μM, 100 μM for 24 hours) dose-dependently restored insulin sensitivity. At 100 μM, insulin (10 nM)-stimulated glucose uptake (measured via [³H]-2-deoxyglucose incorporation) increased by ~75% compared to the H₂O₂-only group, and GLUT4 translocation to the cell membrane (detected by Western blot of membrane fractions) was restored to ~85% of the normal control level. Additionally, Gliclazide (S1702; Diamicron) reversed H₂O₂-induced inhibition of Akt phosphorylation at Ser⁴⁷³: at 100 μM, p-Akt/Akt ratio increased by ~60% vs. the H₂O₂-only group [1] 2. In primary mouse pancreatic beta cells, Gliclazide (S1702; Diamicron) (0.01 μM-10 μM) concentration-dependently blocked KATP channel currents (measured via patch-clamp technique). At 0.1 μM, it inhibited ~50% of basal KATP currents; at 1 μM, the inhibition rate exceeded 90%. In contrast, in primary rat cardiac myocytes and mesenteric arterial smooth muscle cells, even 100 μM Gliclazide (S1702; Diamicron) caused <10% inhibition of KATP currents [2] 3. In 3T3L1 adipocytes, Gliclazide (S1702; Diamicron) (1 μM-100 μM for 24 hours) showed no significant cytotoxicity: cell viability (MTT assay) remained >90% vs. the untreated control [1] |
||
| ln Vivo |
N/A |
||
| Enzyme Assay |
1. KATP channel activity assay in mouse pancreatic beta cells (patch-clamp experiment): Pancreatic islets were isolated from 8-10 week-old C57BL/6 mice by collagenase digestion and density gradient centrifugation. Single beta cells were obtained by trypsinizing islets and plated on glass coverslips for 4 hours. The patch-clamp experiment was performed in whole-cell voltage-clamp mode, with the membrane potential clamped at -70 mV. The extracellular solution contained 119 mM NaCl, 4.7 mM KCl, 1.2 mM MgCl₂, 2.5 mM CaCl₂, and 10 mM HEPES (pH 7.4); the intracellular solution contained 140 mM KCl, 10 mM HEPES, 1 mM MgCl₂, and 5 mM EGTA (pH 7.2). Gliclazide (S1702; Diamicron) was added to the extracellular solution at concentrations of 0.01 μM-100 μM, and KATP currents were recorded after 5 minutes of equilibration for each concentration. The inhibition rate of KATP currents was calculated, and the IC₅₀ was determined by fitting the dose-response curve [2] |
||
| Cell Assay |
1. 3T3L1 adipocyte insulin resistance and glucose uptake assay: 3T3L1 pre-adipocytes were seeded in 6-well plates and cultured in DMEM + 10% FBS until confluence. They were differentiated into mature adipocytes using DMEM containing 10 μg/mL insulin, 1 μM dexamethasone, and 0.5 mM IBMX for 7-10 days. Differentiated adipocytes were treated with 200 μM H₂O₂ for 2 hours to induce insulin resistance, then incubated with Gliclazide (S1702; Diamicron) (10 μM, 100 μM) for 24 hours. For glucose uptake measurement, cells were starved for 4 hours, stimulated with 10 nM insulin for 30 minutes, and then incubated with 0.1 μCi/mL [³H]-2-deoxyglucose for 10 minutes. Cells were washed with cold PBS, lysed, and radioactivity was measured via liquid scintillation counting. For GLUT4 membrane translocation, cell lysates were fractionated by differential centrifugation to isolate membrane fractions, and GLUT4 expression was detected by Western blot (β-actin as the loading control) [1] 2. Mouse pancreatic beta cell isolation and KATP channel assay: Pancreatic islets were isolated from C57BL/6 mice as described in the enzyme assay. Single beta cells were cultured on glass coverslips for 4 hours, then used for patch-clamp experiments (conditions identical to the KATP channel activity assay in Enzyme Assay 1). Current recordings were performed to evaluate the effect of Gliclazide (S1702; Diamicron) on KATP channels [2] |
||
| Animal Protocol |
|
||
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion Rapidly and well absorbed but may have wide inter- and intra-individual variability. Peak plasma concentrations occur within 4-6 hours of oral administration. Metabolites and conjugates are eliminated primarily by the kidneys (60-70%) and also in the feces (10-20%). Metabolism / Metabolites Extensively metabolized in the liver. Less than 1% of the orally administered dose appears unchanged in the urine. Metabolites include oxidized and hydroxylated derivates, as well as glucuronic acid conjugates. Gliclazide has known human metabolites that include Methylhydroxygliclazide, 6-hydroxy-gliclazide, and 7-hydroxy-gliclazide. Biological Half-Life 10.4 hours. Duration of action is 10-24 hours. |
||
| Toxicity/Toxicokinetics |
Protein Binding 94%, highly bound to plasma proteins 1. In vitro toxicity: In 3T3L1 adipocytes, Gliclazide (S1702; Diamicron) (1 μM-100 μM, 24-hour treatment) exhibited no significant cytotoxicity, with cell viability >90% vs. the untreated control (MTT assay) [1] |
||
| References |
[1]. Gliclazide protects 3T3L1 adipocytes against insulin resistance induced by hydrogen peroxide with restoration of GLUT4 translocation. Metabolism, 2006. 55(6): p. 722-30. [2]. Gliclazide produces high-affinity block of KATP channels in mouse isolated pancreatic beta cells but not rat heart or arterial smooth muscle cells. Diabetologia, 2001. 44(8): p. 1019-25. |
||
| Additional Infomation |
Gliclazide is a N-sulfonylurea. It has a role as a hypoglycemic agent, a radical scavenger and an insulin secretagogue. Gliclazide is an oral antihyperglycemic agent used for the treatment of non-insulin-dependent diabetes mellitus (NIDDM). It has been classified differently according to its drug properties in which based on its chemical structure, gliclazide is considered a first-generation sulfonylurea due to the structural presence of a sulfonamide group able to release a proton and the presence of one aromatic group. On the other hand, based on the pharmacological efficacy, gliclazide is considered a second-generation sulfonylurea which presents a higher potency and a shorter half-life. Gliclazide belongs to the sulfonylurea class of insulin secretagogues, which act by stimulating β cells of the pancreas to release insulin. Sulfonylureas increase both basal insulin secretion and meal-stimulated insulin release. Medications in this class differ in their dose, rate of absorption, duration of action, route of elimination and binding site on their target pancreatic β cell receptor. Sulfonylureas also increase peripheral glucose utilization, decrease hepatic gluconeogenesis and may increase the number and sensitivity of insulin receptors. Sulfonylureas are associated with weight gain, though less so than insulin. Due to their mechanism of action, sulfonylureas may cause hypoglycemia and require consistent food intake to decrease this risk. The risk of hypoglycemia is increased in elderly, debilitated and malnourished individuals. Gliclazide has been shown to decrease fasting plasma glucose, postprandial blood glucose and glycosolated hemoglobin (HbA1c) levels (reflective of the last 8-10 weeks of glucose control). Gliclazide is extensively metabolized by the liver; its metabolites are excreted in both urine (60-70%) and feces (10-20%). Gliclazide is a short-acting, relatively high-potency, second-generation sulfonylurea compound with hypoglycemic activity. Gliclazide also increases peripheral insulin sensitivity. This agent is metabolized by CYP2C9. An oral sulfonylurea hypoglycemic agent which stimulates insulin secretion. Drug Indication For the treatment of NIDDM in conjunction with diet and exercise. Mechanism of Action Gliclazide binds to the β cell sulfonyl urea receptor (SUR1). This binding subsequently blocks the ATP sensitive potassium channels. The binding results in closure of the channels and leads to a resulting decrease in potassium efflux leads to depolarization of the β cells. This opens voltage-dependent calcium channels in the β cell resulting in calmodulin activation, which in turn leads to exocytosis of insulin containing secretorty granules. Pharmacodynamics Based on the pharmacological properties, gliclazide is a second generation sulphonylurea which acts as a hypoglycemic agent. It stimulates β cells of the islet of Langerhans in the pancreas to release insulin. It also enhances peripheral insulin sensitivity. Overall, it potentiates insulin release and improves insulin dynamics. 1. Gliclazide (S1702; Diamicron) is a second-generation sulfonylurea oral antidiabetic drug with dual mechanisms of action: (1) blocking pancreatic beta cell KATP channels to promote insulin secretion (supported by [2]); (2) improving insulin sensitivity in insulin-resistant tissues (e.g., adipocytes) by restoring insulin signaling and GLUT4 translocation (supported by [1]) [1], [2] 2. The tissue selectivity of Gliclazide (S1702; Diamicron) for pancreatic beta cell KATP channels (IC₅₀=0.1 μM) over cardiac/ vascular smooth muscle KATP channels (IC₅₀>100 μM) may reduce the risk of cardiovascular side effects compared to non-selective KATP channel blockers [2] 3. In H₂O₂-induced insulin-resistant adipocytes, Gliclazide (S1702; Diamicron) improves glucose transport by restoring GLUT4 membrane translocation rather than upregulating total GLUT4 expression, indicating its regulatory role in GLUT4 trafficking [1] |
Solubility Data
| Solubility (In Vitro) |
|
|||
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (7.73 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 (7.73 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. Solubility in Formulation 3: ≥ 2.5 mg/mL (7.73 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.0921 mL | 15.4603 mL | 30.9205 mL | |
| 5 mM | 0.6184 mL | 3.0921 mL | 6.1841 mL | |
| 10 mM | 0.3092 mL | 1.5460 mL | 3.0921 mL |