DPP4

One brand-new sulfonylurea is glimepiride (Glimepiride). Blood sugar levels in rabbits were lowered by 2.5 times following intravenous treatment of Hoe 490 and by 3.5 times after oral administration of glyburide (HB 419) [1]. Extracellular Aβ40 and Aβ42 levels are lowered by glimepiride (glimeperide). Glimepiride is anticipated to be a good medication for the treatment of AD associated with diabetes [2]. Compared to other sulfonylureas, glimepiride (glimeperide) is typically linked to a decreased risk of hypoglycemia and less weight gain. Since glimepiride (glimeperide) has no negative effects on ischemia preconditioning, it may be safer to use in patients with cardiovascular disease [3].

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Sulfonylureas are a class of antidiabetes medications prescribed to millions of individuals worldwide. Rodents have been used extensively to study sulfonylureas in the laboratory. Here, we report the results of studies treating mice with a sulfonylurea (Glimepiride) in order to understand how the drug affects glucose homeostasis and tolerance. We tested the effect of Glimepiride on fasting blood glucose, glucose tolerance, and insulin secretion, using glimepiride sourced from a local pharmacy. We also examined the effect on glucagon, gluconeogenesis, and insulin sensitivity. Unexpectedly, glimepiride exposure in mice was associated with fasting hyperglycemia, glucose intolerance, and decreased insulin. There was no change in circulating glucagon levels or gluconeogenesis. The effect was dose-dependent, took effect by two weeks, and was reversed within three weeks after removal. Glimepiride elicited the same effects in all strains evaluated: four wild-type strains, as well as the transgenic Grn−/− and diabetic db/db mice. Our findings suggest that the use of glimepiride as a hypoglycemic agent in mice should proceed with caution and may have broader implications about mouse models as a proxy to study the human pharmacopeia.[4]

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Glimepiride Treatment Causes an Impairment in Glucose Tolerance [4]
In order to minimize stress to the animals, we chose to administer Glimepiride in chow. Wild-type C57Bl/6J mice were fed ad libitum with glimepiride chow for two weeks, after which a glucose tolerance test was performed. Glimepiride was well-tolerated, with no significant adverse complications , including no observed hypoglycemic events. Glimepiride treatment did not cause a change in weight (not shown). Contrary to published reports, glimepiride treatment increased fasting blood glucose and blood glucose at most of the time points after glucose injection (Figure 1(a)), at least at 8 mg/kg/day. There was also an increase in the area under the curve for the time course, indicative of impaired glucose tolerance (Figure 1(b)). The lower dose (1 mg/kg/day) trended toward an increase in the area under the curve (p = 0.07).

β-Secretase enzyme activity assay [2]
β-Secretase activity present in cells treated with or without different concentrations of Glimepiride was measured by using a β-secretase fluorometric assay kit according to the manufacturer's instructions. Briefly, the cells were washed twice with PBS, and 60 μl extraction buffer was added to the dish. After 5 min incubation on ice, the extract was centrifuged at 10,000 × g for 5 min. 50 μl of supernatant was mixed with an equal volume of 2× reaction buffer and 2 μl substrate. The plate was kept in the dark at 37 °C for 90 min, and the fluorescence was recorded using a microplate reader. The protein concentrations were quantified by BCA method and an equal amount of cellular protein was used for measuring β-secretase activity.

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γ-Secretase cell-free assay [2]
γ-Secretase cell-free assay was performed as described previously. Briefly, rat cortex was homogenized with 15 stokes of pestle A, and postnuclear fractions were isolated by centrifugation (800 × g for 10 min). The supernatants were centrifuged at 25,000 × g for 1 h at 4 °C and the membrane pellets were solubilized in reaction buffer containing 50 mM Tris–HCl, pH 6.8, 2 mM EDTA, 150 mM KCl, and 0.25% CHAPS. Solubilized membranes (30 μg) and γ-secretase fluorogenic substrate were incubated at 37 °C for 7 h in the absence or presence of Glimepiride before fluorescence measurement.

Aβ40 and Aβ42 enzyme-linked immunosorbent assay (ELISA) [2]
For measurement of extracellular Aβ40 and Aβ42 levels, conditioned media from drug-treated and untreated cells were harvested and debris was removed by centrifugation before applying to ELISA plates. Aβ40 and Aβ42 levels were quantified using the Human/Rat Aβ40 ELISA Kit and the Human/Rat Aβ42 ELISA Kit in accordance with the manufacturer's instructions, respectively.

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Western blotting Cells were washed with PBS and lysed in RIPA (50 mM Tris, pH 7.4, 150 mM NaCl, 1% NP-40, 0.5% sodium deoxycholate, 0.1% SDS, supplemented with a protease inhibitor mixture). The levels of BACE1 and β-actin antibody in the cell lysates were quantified by Western blot analysis using monoclonal anti-BACE1 C-terminal antibody (1:500) and monoclonal anti-β-actin antibody (1:5000), respectively. A standard ECL detection procedure was then used and relative absorbance of the resultant bands was determined using the Quantity One imaging system.

Information about the mouse strains used, including age, length of treatment, and tests performed, is summarized in Table 1. All strains were obtained from the Jackson Labs (C57Bl/6J, C57Bl/6N, BalbC, and C3H) or in-house breeding colonies at the University of Kentucky (Grn−/− [10, 11] and db/db). db/db mice were on a hybrid C57Bl/6J/CD-1/129 background, described previously. Mice were group housed, fed and provided with water ad libitum, and maintained on a constant 12-hour light/dark cycle. Glimepiride was obtained by prescription and milled into chow (1 or 8 mg/kg/day). We based our estimate of Glimepiride dose on a 25 g mouse, and an average food consumption of 5 g per day. Nicorandil was administered in drinking water (15 mg/kg/day), based on an average of 5 mL of water consumed per day. Control mice were fed a control dietwith a consistent nutrient content and given control water with no additives. For the wash-out experiment, mice were tested three weeks after removal of Glimepiride chow. Mice were euthanized by CO2 asphyxiation, followed by decapitation, and the liver and serum frozen until use.[4]

Absorption and Distribution
• Absorption: Orally administered drugs are 100% absorbed in the gastrointestinal tract, primarily in the upper segment of the small intestine, with a bioavailability of approximately 80%8. The time to peak plasma concentration (Cmax) is 2-3 hours
• Protein Binding Rate: Exceeds 99.5%, indicating high plasma protein binding

Metabolism and Excretion
• Metabolic Pathway: Complete metabolism occurs via hepatic oxidative biotransformation, primarily yielding two metabolites:
o Cyclohexyl hydroxymethyl derivative (M1): Retains about 1/3 of pharmacological activity
o Carboxylated derivative (M2): Exhibits no hypoglycemic activity
• Half-Life: Approximately 5 hours, but the duration of action can extend up to 24 hours

Other Characteristics
• Dosage Range: 1.0–8.0 mg/day, adjusted to the minimum effective dose based on blood glucose levels

Tissue Distribution: Higher concentrations are observed in the liver, kidneys, and muscles

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Metabolism / Metabolites
Glimepiride has known human metabolites that include Cyclohexylhydroymethylglimepiride.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Because no information is available on the use of glimepiride during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant. Monitor breastfed infants for signs of hypoglycemia such as jitteriness, excessive sleepiness, poor feeding, seizures cyanosis, apnea, or hypothermia. If there is concern, monitoring of the breastfed infant's blood glucose is advisable during maternal therapy with glimepiride.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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3476 man TDLo oral 28 ug/kg/2D-I BLOOD: HEMORRHAGE; BLOOD: THROMBOCYTOPENIA; SKIN AND APPENDAGES (SKIN): DERMATITIS, OTHER: AFTER SYSTEMIC EXPOSURE Annals of Pharmacotherpy., 34(120), 2000
3476 rat LD oral >10 gm/kg LIVER: OTHER CHANGES Arzneimittel-Forschung. Drug Research., 43(547), 1993 [PMID:8328999]
3476 rat LD intraperitoneal >3950 mg/kg LIVER: OTHER CHANGES Arzneimittel-Forschung. Drug Research., 43(547), 1993 [PMID:8328999]
3476 rat LD50 unreported >10 gm/kg Diabetes Frontier., 3(565), 1992
3476 mouse LD50 unreported >10 gm/kg Diabetes Frontier., 3(565), 1992

[1]. Special pharmacology of the new sulfonylurea glimepiride. Arzneimittelforschung, 1988. 38(8): p. 1120-30.

[2]. Glimepiride attenuates Abeta production via suppressing BACE1 activity in cortical neurons. Neurosci Lett, 2013. 557 Pt B: p. 90-4.

[3]. Glimepiride: evidence-based facts, trends, and observations (GIFTS). [corrected]. Vasc Health Risk Manag, 2012. 8: p. 463-72.

[4]. Glimepiride Administered in Chow Reversibly Impairs Glucose Tolerance in Mice. J Diabetes Res. 2018 Oct 29;2018:1251345.

Glimepiride is a sulfonamide, a N-acylurea and a N-sulfonylurea. It has a role as a hypoglycemic agent and an insulin secretagogue.
Glimepiride is a Sulfonylurea.
See also: Glimepiride (annotation moved to).

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Numerous lines of evidence suggest a strong link between diabetes mellitus and Alzheimer's disease (AD). Impaired insulin signaling and insulin resistance occur not only in diabetes but also in the brain of AD. Recent evidence has indicated that peroxisome proliferator-activated receptor γ (PPARγ) agonists thiazolidinediones (TZDs) can decrease β-amyloid peptide (Aβ) deposition, which is the core component of senile plaques in AD, but the underlying mechanisms still remain unclear. In this study, we investigated whether glimepiride with PPARγ-stimulating activity, an oral anti-diabetic drug, has similar effects on Aβ production in primary cortical neurons. We demonstrated that glimepiride decreased extracellular Aβ40 and Aβ42 levels. The effect of glimepiride on reduction of Aβ40 generation was mediated by downregulation of β-site APP-cleaving enzyme 1 (BACE1) mRNA and protein expression, and by suppression of BACE1 activity. In addition, we found that high glucose condition enhanced Aβ40 production and glimepiride significantly decreased high glucose-induced Aβ40 production. Finally, a specific PPARγ antagonist GW9662 reversed glimepiride inhibitory effect on Aβ40 generation, suggesting a PPARγ-dependent mechanism may be involved. Our data indicated that glimepiride may serve as a promising drug for the treatment of AD associated with diabetes.[2]

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Type 2 diabetes mellitus is characterized by insulin resistance and progressive β cell failure; therefore, β cell secretagogues are useful for achieving sufficient glycemic control. Glimepiride is a second-generation sulfonylurea that stimulates pancreatic β cells to release insulin. Additionally, is has been shown to work via several extra pancreatic mechanisms. It is administered as monotherapy in patients with type 2 diabetes mellitus in whom glycemic control is not achieved by dietary and lifestyle modifications. It can also be combined with other antihyperglycemic agents, including metformin and insulin, in patients who are not adequately controlled by sulfonylureas alone. The effective dosage range is 1 to 8 mg/day; however, there is no significant difference between 4 and 8 mg/day, but it should be used with caution in the elderly and in patients with renal or hepatic disease. In clinical studies, glimepiride was generally associated with lower risk of hypoglycemia and less weight gain compared to other sulfonylureas. Glimepiride use may be safer in patients with cardiovascular disease because of its lack of detrimental effects on ischemic preconditioning. It is effective in reducing fasting plasma glucose, post-prandial glucose, and glycosylated hemoglobin levels and is a useful, cost-effective treatment option for managing type 2 diabetes mellitus.[3]

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Sulfonylureas are a class of antidiabetes medications prescribed to millions of individuals worldwide. Rodents have been used extensively to study sulfonylureas in the laboratory. Here, we report the results of studies treating mice with a sulfonylurea (glimepiride) in order to understand how the drug affects glucose homeostasis and tolerance. We tested the effect of glimepiride on fasting blood glucose, glucose tolerance, and insulin secretion, using glimepiride sourced from a local pharmacy. We also examined the effect on glucagon, gluconeogenesis, and insulin sensitivity. Unexpectedly, glimepiride exposure in mice was associated with fasting hyperglycemia, glucose intolerance, and decreased insulin. There was no change in circulating glucagon levels or gluconeogenesis. The effect was dose-dependent, took effect by two weeks, and was reversed within three weeks after removal. Glimepiride elicited the same effects in all strains evaluated: four wild-type strains, as well as the transgenic Grn−/− and diabetic db/db mice. Our findings suggest that the use of glimepiride as a hypoglycemic agent in mice should proceed with caution and may have broader implications about mouse models as a proxy to study the human pharmacopeia.[4]

C24H34N4O5S

490.62

490.224

C, 58.75; H, 6.99; N, 11.42; O, 16.31; S, 6.54

93479-97-1

Glimepiride-d5;1028809-90-6; Glimepiride-d4-1; 1131981-29-7; 119018-30-3 (urethane); 119018-29-0 (sulfonamide); 93479-97-1

3476

White to off-white solid powder

1.3±0.1 g/cm3

677.0±65.0 °C at 760 mmHg

212.2-214.5 °C

363.2±34.3 °C

0.0±2.2 mmHg at 25°C

1.628

4.17

3

5

7

34

895

0

CCC1=C(CN(C1=O)C(=O)NCCC2=CC=C(C=C2)S(=O)(=O)NC(=O)NC3CCC(CC3)C)C

WIGIZIANZCJQQY-UHFFFAOYSA-N

InChI=1S/C24H34N4O5S/c1-4-21-17(3)15-28(22(21)29)24(31)25-14-13-18-7-11-20(12-8-18)34(32,33)27-23(30)26-19-9-5-16(2)6-10-19/h7-8,11-12,16,19H,4-6,9-10,13-15H2,1-3H3,(H,25,31)(H2,26,27,30)

4-ethyl-3-methyl-N-[2-[4-[(4-methylcyclohexyl)carbamoylsulfamoyl]phenyl]ethyl]-5-oxo-2H-pyrrole-1-carboxamide

HOE-490; Glimepiride; HOE 490; glimepiride; 93479-97-1; Amaryl; Glimepirida; Amarel; Glimepirid; Glimepiridum; Hoe-490; HOE-490; Amaryl; Glimepiridum; Amarel; Glimepirida; Roname

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 (5.10 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
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 (5.10 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.)