Glibenclamide

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Not to be confused with gliclazide or glipizide.
Glibenclamide
Glibenclamide structural formula V.1.svg
Glibenclamide 3D.png
Systematic (IUPAC) name
5-chloro-N-(4-[N-(cyclohexylcarbamoyl)sulfamoyl]phenethyl)-2-methoxybenzamide
Clinical data
Trade names Diabeta, Glynase, Micronase Daonil, Semi-Daonil, Euglucon, Delmide
AHFS/Drugs.com International Drug Names
MedlinePlus a684058
Licence data US FDA:link
Pregnancy cat.
Legal status
Routes Oral
Pharmacokinetic data
Protein binding Extensive
Metabolism Hepatic hydroxylation (CYP2C9-mediated)
Half-life 10 hours
Excretion Renal and biliary
Identifiers
CAS number 10238-21-8 YesY
ATC code A10BB01
PubChem CID 3488
IUPHAR ligand 2414
DrugBank DB01016
ChemSpider 3368 YesY
UNII SX6K58TVWC YesY
KEGG D00336 YesY
ChEBI CHEBI:5441 YesY
ChEMBL CHEMBL472 YesY
Chemical data
Formula C23H28ClN3O5S 
Mol. mass 494.004 g/mol
 YesY (what is this?)  (verify)

Glibenclamide (INN), also known as glyburide (USAN), is an antidiabetic drug in a class of medications known as sulfonylureas, closely related to sulfa drugs. It was developed in 1966 in a cooperative study between Boehringer Mannheim (now part of Roche) and Hoechst (now part of Sanofi-Aventis).[1]

It is sold in doses of 1.25, 2.5, and 5 mg, under the trade names Diabeta, Glynase, and Micronase in the United States and Daonil, Semi-Daonil, and Euglucon in the United Kingdom, and Delmide in India. It is also sold in combination with metformin under the trade names Glucovance, Benimet, and Glibomet, as well as Glucored and Glucored Forte (by Sun Pharmaceutical) in Russia, Belarus and other countries of the CIS.

Mechanism of action[edit]

The drug works by binding to and activating the ATP-sensitive potassium channels (KATP) inhibitory regulatory subunit sulfonylurea receptor 1 (SUR1) [2] in pancreatic beta cells. This inhibition causes cell membrane depolarization, opening voltage-dependent calcium channels. This results in an increase in intracellular calcium in the beta cell and subsequent stimulation of insulin release.

After a cerebral ischemic insult, the blood–brain barrier is broken and glibenclamide can reach the central nervous system. Glibenclamide has been shown to bind more efficiently to the ischemic hemisphere.[3] Moreover, under ischemic conditions SUR1, the regulatory subunit of the KATP- and the NCCa-ATP-channels, is expressed in neurons, astrocytes, oligodendrocytes, endothelial cells[4] and by reactive microglia.[3]

Medical uses[edit]

It is used in the treatment of type 2 diabetes. As of 2011, it is one of only two oral antidiabetics in the World Health Organization Model List of Essential Medicines (the other being metformin).[5] As of 2003, in the United States, it was the most popular sulfonylurea.[6]

Side effects and contraindications[edit]

This drug is a major cause of drug induced hypoglycemia. The risk is increased against other sulfonylureas.[7] Cholestatic jaundice is noted.

Glibenclamide may be contraindicated in those with G6PD deficiency, as it may cause acute haemolysis.[8]

Recently published data suggest glibenclamide is associated with significantly higher annual mortality when combined with metformin than other insulin-secreting medications, after correcting for other potentially confounding patient characteristics. The safety of this combination has been questioned.[9] Glibenclamide causes cholestasis as the major side effect.

Synthesis[edit]

The N-acetyl derivative of β-phenethylamine is reacted with chlorosulfonic acid to form the para sulfonyl chloride derivative. This is then subjected to ammonolysis, followed by base-catalyzed removal of the acetamide. This is then acylated with 2-methoxy-5-chlorobenzoic acid chloride to give the amide intermediate. This is then reacted with cyclohexyl isocyanate to yield the sulfonylurea glibenclamide.

Glibenclamide synthesis 1:[10]
Glyburide synthesis 2:[11] Hoechst DE 1283837  DE 1301812  BE 684652 

Analogs[edit]

Additional glibenclamide structural analogs have been prepared by Ahmadi et al.[12]

Research[edit]

Glibenclamide improves outcome in animal stroke models by preventing brain swelling[13] and enhancing neuroprotection.[2] A retrospective study showed, in type 2 diabetic patients already taking glyburide, NIH stroke scale scores on were improved on discharge compared to diabetic patients not taking glyburide.[14]

See also[edit]

References[edit]

  1. ^ Marble A (1971). "Glibenclamide, a new sulphonylurea: whither oral hypoglycaemic agents?". Drugs 1 (2): 109–15. doi:10.2165/00003495-197101020-00001. PMID 4999930. 
  2. ^ a b Serrano-Martín X, Payares G, Mendoza-León A (December 2006). "Glibenclamide, a blocker of K+(ATP) channels, shows antileishmanial activity in experimental murine cutaneous leishmaniasis". Antimicrob. Agents Chemother. 50 (12): 4214–6. doi:10.1128/AAC.00617-06. PMC 1693980. PMID 17015627. 
  3. ^ a b Ortega FJ, Gimeno-Bayon J, Espinosa-Parrilla JF, Carrasco JL, Batlle M, Pugliese M, Mahy N, Rodríguez MJ (May 2012). "ATP-dependent potassium channel blockade strengthens microglial neuroprotection after hypoxia-ischemia in rats". Exp. Neurol. 235 (1): 282–96. doi:10.1016/j.expneurol.2012.02.010. PMID 22387180. 
  4. ^ Simard JM, Woo SK, Schwartzbauer GT, Gerzanich V (September 2012). "Sulfonylurea receptor 1 in central nervous system injury: a focused review". J. Cereb. Blood Flow Metab. 32 (9): 1699–717. doi:10.1038/jcbfm.2012.91. PMC 3434627. PMID 22714048. 
  5. ^ WHO Expert Committee (March 2011). "The selection and use of essential medicines". World Health Organ Tech Rep Ser (965): i–xiv, 1–249. PMID 22891532. 
  6. ^ Riddle MC (February 2003). "Editorial: sulfonylureas differ in effects on ischemic preconditioning--is it time to retire glyburide?". J. Clin. Endocrinol. Metab. 88 (2): 528–30. doi:10.1210/jc.2002-021971. PMID 12574174. 
  7. ^ Gangji, A. S.; Cukierman, T.; Gerstein, H. C.; Goldsmith, C. H.; Clase, C. M. (1 February 2007). "A Systematic Review and Meta-Analysis of Hypoglycemia and Cardiovascular Events: A comparison of glyburide with other secretagogues and with insulin". Diabetes Care 30 (2): 389–394. doi:10.2337/dc06-1789. 
  8. ^ Meloni G, Meloni T (January 1996). "Glyburide-induced acute haemolysis in a G6PD-deficient patient with NIDDM". Br. J. Haematol. 92 (1): 159–60. doi:10.1046/j.1365-2141.1996.275810.x. PMID 8562390. 
  9. ^ Monami M, Luzzi C, Lamanna C, Chiasserini V, Addante F, Desideri CM, Masotti G, Marchionni N, Mannucci E (2006). "Three-year mortality in diabetic patients treated with different combinations of insulin secretagogues and metformin". Diabetes Metab Res Rev 22 (6): 477–82. doi:10.1002/dmrr.642. PMID 16634115. 
  10. ^ Hsi, R. S. P. (1973). "Synthesis of carbon-14 and tritium labeled glyburide". Journal of Labelled Compounds 9: 91. doi:10.1002/jlcr.2590090112.  edit
  11. ^ Arzneim-Forsch 16, 1640 (1966).
  12. ^ Ahmadi, A; Khalili, M; Khatami, K; Farsadrooh, M; Nahri-Niknafs, B (2014). "Synthesis and investigating hypoglycemic and hypolipidemic activities of some glibenclamide analogues in rats". Mini reviews in medicinal chemistry 14 (2): 208–13. PMID 24387708.  edit
  13. ^ Simard JM, Chen M, Tarasov KV, Bhatta S, Ivanova S, Melnitchenko L, Tsymbalyuk N, West GA, Gerzanich V (April 2006). "Newly expressed SUR1-regulated NC(Ca-ATP) channel mediates cerebral edema after ischemic stroke". Nat. Med. 12 (4): 433–40. doi:10.1038/nm1390. PMC 2740734. PMID 16550187. 
  14. ^ Kunte H, Schmidt S, Eliasziw M, del Zoppo GJ, Simard JM, Masuhr F, Weih M, Dirnagl U (September 2007). "Sulfonylureas improve outcome in patients with type 2 diabetes and acute ischemic stroke". Stroke 38 (9): 2526–30. doi:10.1161/STROKEAHA.107.482216. PMC 2742413. PMID 17673715.