Vildagliptin

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Vildagliptin
Skeletal formula
Ball-and-stick model
Systematic (IUPAC) name
(S)-1-[N-(3-hydroxy-1-adamantyl)glycyl]pyrrolidine-2-carbonitrile
Clinical data
Trade names Galvus
AHFS/Drugs.com International Drug Names
Licence data EMA:Link
Pregnancy cat. Not recommended
Legal status POM (UK)
Routes Oral
Pharmacokinetic data
Bioavailability 85%
Protein binding 9.3%
Metabolism Mainly hydrolysis to inactive metabolite; CYP450 not appreciably involved
Half-life 2 to 3 hours
Excretion Renal
Identifiers
CAS number 274901-16-5 N
ATC code A10BH02
A10BD08 (with metformin)[1]
PubChem CID 6918537
DrugBank DB04876
ChemSpider 5293734 YesY
UNII I6B4B2U96P YesY
KEGG D07080 YesY
ChEMBL CHEMBL142703 YesY
Synonyms (2S)-1-{2-[(3-hydroxy-1-adamantyl)amino]acetyl}pyrrolidine-2-carbonitrile
Chemical data
Formula C17H25N3O2 
Mol. mass 303.399 g/mol
 N (what is this?)  (verify)

Vildagliptin (previously LAF237, trade names Galvus, Zomelis, Jalra) 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]

Vildagliptin is an unique molecule with dual nature as it manages the glucagon levels in hypoglycemia as well as hyperglycemia.

Combination with metformin[edit]

The EMEA has also approved a new oral treatment released by Novartis, called Eucreas, a combination of vildagliptin and metformin.[4]

Adverse Effects[edit]

Adverse effects observed in clinical trials include nausea, hypoglycemia, tremor, headache and dizziness. Rare cases of hepatoxicity have been reported.[5]

There have been case reports of pancreatitis associated with DPP-IV inhibitors. A group at UCLA reported increased pre-cancerous pancreatic changes in rats and in human organ donors who had been treated with DPP-IV inhibitors.[6][7] In response to these reports, the United States FDA and the European Medicines Agency each undertook independent reviews of all clinical and preclinical data related to the possible association of DPP-IV inhibitors with pancreatic cancer. In a joint letter to the New England Journal of Medicines, the agencies stated that "Both agencies agree that assertions concerning a causal association between incretin-based drugs and pancreatitis or pancreatic cancer, as expressed recently in the scientific literature and in the media, are inconsistent with the current data. The FDA and the EMA have not reached a final conclusion at this time regarding such a causal relationship. Although the totality of the data that have been reviewed provides reassurance, pancreatitis will continue to be considered a risk associated with these drugs until more data are available; both agencies continue to investigate this safety signal."[8]


Synthetic Chemistry[edit]

Vildagliptin synth.png

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[9]

The final Structure (cyclopentane part) is missing a nitrogen atom

See also[edit]

References[edit]

  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. ^ EU approves Novartis's Eucreas diabetes drug. Reuters, February 25, 2008.
  5. ^ "www.ema.europa.eu". 
  6. ^ Matveyenko AV, Dry S, Cox HI, et al. (July 2009). "Beneficial endocrine but adverse exocrine effects of sitagliptin in the human islet amyloid polypeptide transgenic rat model of type 2 diabetes: interactions with metformin". Diabetes 58 (7): 1604–15. doi:10.2337/db09-0058. PMC 2699878. PMID 19403868. 
  7. ^ Butler AE, Campbell-Thompson M, Gurlo T, Dawson DW, Atkinson M, Butler PC (July 2013). "Marked expansion of exocrine and endocrine pancreas with incretin therapy in humans with increased exocrine pancreas dysplasia and the potential for glucagon-producing neuroendocrine tumors". Diabetes 62 (7): 2595–604. doi:10.2337/db12-1686. PMID 23524641. 
  8. ^ Egan, Amy G.; Blind, Eberhard; Dunder, Kristina; De Graeff, Pieter A.; Hummer, B. Timothy; Bourcier, Todd; Rosebraugh, Curtis (2014). "Pancreatic Safety of Incretin-Based Drugs — FDA and EMA Assessment — NEJM". New England Journal of Medicine 370 (9): 794–7. doi:10.1056/NEJMp1314078. PMID 24571751. 
  9. ^ 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[edit]