Vildagliptin

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{{Drugbox | Verifiedfields = changed | verifiedrevid = 470630169 | IUPAC_name = (S)-1-[N-(3-hydroxy-1-adamantyl)glycyl]pyrrolidine-2-carbonitrile | image = Vildagliptin Structural Formulae.png | alt = Skeletal formula | image2 = Vildagliptin-3D-balls.png | alt2 = Ball-and-stick model

| tradename = | Drugs.com = International Drug Names | licence_EU = Galvus | pregnancy_category = Not recommended | legal_UK = POM | legal_status = | routes_of_administration = Oral

| bioavailability = 85% | protein_bound = 9.3% | metabolism = Mainly hydrolysis to inactive metabolite; CYP450 not appreciably involved | elimination_half-life = 2 to 3 hours | excretion = Renal

| CAS_number_Ref =  ☒N | CAS_number = 274901-16-5 | ATC_prefix = A10 | ATC_suffix = BH02 | ATC_supplemental =
A10BD08 (WHO) (with metformin)[1] | PubChem = 6918537 | DrugBank_Ref =  checkY | DrugBank = DB04876 | ChemSpiderID_Ref =  checkY | ChemSpiderID = 5293734 | UNII_Ref =  checkY | UNII = I6B4B2U96P | KEGG_Ref =  checkY | KEGG = D07080 | ChEMBL_Ref =  checkY | ChEMBL = 142703

| C=17 | H=25 | N=3 | O=2 | molecular_weight = 303.399 g/mol | smiles = N#C[C@H]4N(C(=O)CNC13CC2CC(C1)CC(O)(C2)C3)CCC4 | InChI = 1/C17H25N3O2/c18-9-14-2-1-3-20(14)15(21)10-19-16-5-12-4-13(6-16)8-17(22,7-12)11-16/h12-14,19,22H,1-8,10-11H2/t12?,13?,14-,16?,17?/m0/s1 | InChIKey = SYOKIDBDQMKNDQ-XWTIBIIYBW | StdInChI_Ref =  checkY | StdInChI = 1S/C17H25N3O2/c18-9-14-2-1-3-20(14)15(21)10-19-16-5-12-4-13(6-16)8-17(22,7-12)11-16/h12-14,19,22H,1-8,10-11H2/t12?,13?,14-,16?,17?/m0/s1 | StdInChIKey_Ref =  checkY | StdInChIKey = SYOKIDBDQMKNDQ-XWTIBIIYSA-N | synonyms = (2S)-1-{2-[(3-hydroxy-1-adamantyl)amino]acetyl}pyrrolidine-2-carbonitrile }} Vildagliptin (previously identified as LAF237, trade names Zomelis, Galvus) is an oral anti-hyperglycemic agent (anti-diabetic drug) of the new dipeptidyl peptidase-4 (DPP-4) inhibitor class of drugs. Vildagliptin inhibits the inactivation of GLP-1[2][3] and GIP[3] by DPP-4, allowing GLP-1 and GIP to potentiate the secretion of insulin in the beta cells and suppress glucagon release by the alpha cells of the islets of Langerhans in the pancreas.

Vildagliptin has been shown to reduce hyperglycemia in type 2 diabetes mellitus.[2]

Novartis has since withdrawn its intent to submit vildagliptin to the FDA, as of July 2008.[4] The Food and Drug Administration had demanded additional clinical data before it could approve vildagliptin including extra evidence that skin lesions and kidney impairment seen during an early study on animals have not occurred in human trials.

While the drug is still not approved for use in the US, it was approved in Feb 2008 by European Medicines Agency for use within the EU[5] and is listed on the Australian PBS with certain restrictions.[6]

Combination with metformin

The EMEA has also approved a new oral treatment released by Novartis, called Eucreas, a combination of vildagliptin and metformin.[7]

Cancer risk of DPP-4 inhibitors

The DPP-4 enzyme is known to be involved in the suppression of certain malignancies, particularly in limiting the tissue invasion of these tumours. Inhibiting the DPP-4 enzymes may allow some cancers to progress.[8][9] A study of DPP-4 inhibition in human non-small cell lung cancer (NSCLC) concluded that "DPPIV functions as a tumor suppressor, and its downregulation may contribute to the loss of growth control in NSCLC cells.[10]

The risk of cancer suppression with DPP-4 down-regulation applies to all the DPP-4 inhibitors on the market in addition to vildagliptin (sitagliptin and saxagliptin)

Synthetic Chemistry

Source: 1-[[(3-Hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidine: A Potent, Selective, and Orally Bioavailable Dipeptidyl Peptidase IV Inhibitor with Antihyperglycemic Properties[11]

See also

References

  1. ^ WHO International Working Group for Drug Statistics Methodology (August 27, 2008). "ATC/DDD Classification (FINAL): New ATC 5th level codes". WHO Collaborating Centre for Drug Statistics Methodology. Retrieved 2008-09-05.
  2. ^ a b Ahrén, B; Landin-Olsson, M; Jansson, PA; Svensson, M; Holmes, D; Schweizer, A (2004). "Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and reduces glucagon levels in type 2 diabetes". The Journal of Clinical Endocrinology and Metabolism. 89 (5): 2078–84. doi:10.1210/jc.2003-031907. PMID 15126524.
  3. ^ a b Mentlein, R; Gallwitz, B; Schmidt, WE (1993). "Dipeptidyl-peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon-like peptide-1(7-36)amide, peptide histidine methionine and is responsible for their degradation in human serum". European journal of biochemistry / FEBS. 214 (3): 829–35. doi:10.1111/j.1432-1033.1993.tb17986.x. PMID 8100523.
  4. ^ Focus on Health: Drug makers say FDA slows U.S. pipeline --- Emphasis on safety, side effects grows; swing of pendulum? By Avery Johnson and Ron Winslow 2180 words 2 July 2008 The Wall Street Journal Europe
  5. ^ EU approves Novartis diabetes drug Galvus.Reuters, February 01, 2008
  6. ^ NPS - better medicines, better health (August 2010). "Vildagliptin for type 2 diabetes". Retrieved 27 August 2010.
  7. ^ EU approves Novartis's Eucreas diabetes drug. Reuters, February 25, 2008.
  8. ^ Pro B, Dang NH (2004). "CD26/dipeptidyl peptidase IV and its role in cancer". Histol. Histopathol. 19 (4): 1345–51. PMID 15375776. {{cite journal}}: Unknown parameter |month= ignored (help)
  9. ^ Wesley UV, McGroarty M, Homoyouni A (2005). "Dipeptidyl peptidase inhibits malignant phenotype of prostate cancer cells by blocking basic fibroblast growth factor signaling pathway". Cancer Res. 65 (4): 1325–34. doi:10.1158/0008-5472.CAN-04-1852. PMID 15735018. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  10. ^ Wesley, U (2004). "Role for dipeptidyl peptidase IV in tumor suppression of human non small cell lung carcinoma cells". Int J Cancer. 109 (6): 855–866. doi:10.1002/ijc.20091. PMID 15027119. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  11. ^ Villhauer, Edwin B.; Brinkman, John A.; Naderi, Goli B.; Burkey, Bryan F.; Dunning, Beth E.; Prasad, Kapa; Mangold, Bonnie L.; Russell, Mary E.; Hughes, Thomas E. (2003). "1-(3-hydroxy-1-adamantyl)aminoacetyl-2-cyano-(S)-pyrrolidine: a potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitor with antihyperglycemic properties". Journal of Medicinal Chemistry. 46 (13): 2774–89. doi:10.1021/jm030091l. PMID 12801240.

External links

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