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]

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].

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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]

N/A

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]

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]

Absorption, Distribution and Excretion
Absorption is rapid and good, but significant inter- and intra-individual variability may exist. Peak plasma concentrations are reached within 4–6 hours after oral administration. Metabolites and conjugates are primarily excreted via the kidneys (60–70%), with a partial excretion via feces (10–20%). Metabolisms/Metabolites Extensively metabolized in the liver. Less than 1% of the oral dose is excreted unchanged in the urine. Metabolites include oxidized and hydroxylated derivatives, as well as glucuronide conjugates. Known metabolites of gliclazide include methylhydroxygliclazide, 6-hydroxygliclazide, and 7-hydroxygliclazide. Biological Half-Life 10.4 hours. Duration of action is 10–24 hours.

Protein binding
94%, highly bound to plasma proteins

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1. In vitro toxicity: In 3T3L1 adipocytes, Gliclazide (S1702; Diamicron) (1 μM-100 μM, treated for 24 hours) did not show significant cytotoxicity, and cell viability was >90% (compared to the untreated control group, MTT assay)[1]

[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.

Gliclazide is an N-sulfonylurea drug. It has the effects of lowering blood glucose, scavenging free radicals, and promoting insulin secretion. Gliclazide is an oral hypoglycemic agent used to treat non-insulin-dependent diabetes mellitus (NIDDM). Based on its pharmacological properties, gliclazide is classified into different categories. Based on its chemical structure, due to the presence of a proton-releasing sulfonamide group and an aromatic group, gliclazide is considered a first-generation sulfonylurea. On the other hand, based on its pharmacological efficacy, gliclazide is considered a second-generation sulfonylurea, with higher potency and a shorter half-life. Gliclazide belongs to the sulfonylurea class of insulin secretagogues, and its mechanism of action is through stimulating the release of insulin from pancreatic β-cells. Sulfonylureas can increase basal insulin secretion and postprandial insulin secretion. These drugs differ in dosage, absorption rate, duration of action, elimination pathway, and binding sites targeting pancreatic β-cell receptors. Sulfonylureas can also increase peripheral glucose utilization, reduce hepatic gluconeogenesis, and may increase the number and sensitivity of insulin receptors. Sulfonylureas are associated with weight gain, but to a lesser extent than insulin. Due to their mechanism of action, sulfonylureas can cause hypoglycemia, thus requiring continuous food intake to reduce this risk. The risk of hypoglycemia is higher in the elderly, the frail, and those who are malnourished. Gliclazide has been shown to lower fasting blood glucose, postprandial blood glucose, and glycated hemoglobin (HbA1c) levels (reflecting glycemic control over the past 8-10 weeks). Gliclazide is primarily metabolized in the liver; its metabolites are mainly excreted in urine (60-70%) and feces (10-20%). Gliclazide is a short-acting, relatively potent second-generation sulfonylurea compound with hypoglycemic activity. Gliclazide also improves peripheral insulin sensitivity. This drug is metabolized by CYP2C9. An oral sulfonylurea hypoglycemic agent that stimulates insulin secretion. Indications: For the treatment of non-insulin-dependent diabetes mellitus (NIDDM), requiring dietary and exercise regimens. Mechanism of Action Gliclazide binds to the sulfonylurea receptor (SUR1) on β-cells. This binding subsequently blocks ATP-sensitive potassium channels. Binding leads to channel closure, resulting in reduced potassium ion efflux and consequently β-cell depolarization. This opens voltage-dependent calcium channels in β-cells. Cellular activation leads to calmodulin activation, which in turn causes exocytosis of insulin-containing secretory granules. Pharmacodynamics Based on its pharmacological properties, gliclazide is a second-generation sulfonylurea hypoglycemic agent. It stimulates the release of insulin from pancreatic β-cells and enhances peripheral insulin sensitivity. Overall, it enhances insulin release and improves insulin dynamics.

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1. Gliclazide (S1702; Diamicron) is a second-generation sulfonylurea oral hypoglycemic agent with a dual mechanism of action: (1) blocking pancreatic β-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 (reference [1]). [1], [2]
2. Gliclazide (S1702; Diamicron) has a higher tissue selectivity (IC₅₀=0.1 μM) for pancreatic β-cell KATP channels than for cardiac/vascular smooth muscle KATP channels (IC₅₀>100 μM), which 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 insulin sensitivity in insulin-resistant tissues (e.g., adipocytes) by restoring GLUT4 translocation and GLUT4 translocation. Membrane translocation, rather than upregulation of total GLUT4 expression, improves glucose transport, suggesting that GLUT4 plays a regulatory role in GLUT4 transport [1]

C15H21N3O3S

323.41

323.13

21187-98-4

Gliclazide-d4;1185039-30-8

3475

White to off-white solid powder

1.4±0.1 g/cm3

163-169 °C(lit.)

1.624

1.57

2

4

3

22

497

0

BOVGTQGAOIONJV-UHFFFAOYSA-N

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)

1-(3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl)-3-(4-methylphenyl)sulfonylurea

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

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.

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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.

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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.

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 (Please use freshly prepared in vivo formulations for optimal results.)