Denufosol

Denufosol
Denufosol
Denufosol tetrasodium
Systematic (IUPAC) name
[[(3S,5R)-5-(4-amino-2-oxopyrimidin-1-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate
Clinical data
Pregnancy cat.  ?
Legal status Investigational
Routes Inhalation
Identifiers
CAS number 211448-85-0
ATC code None
PubChem CID 192708
UNII 5PC250KSSH YesY
Synonyms INS37217
2'-Desoxycytidine (5')tetraphospho(5')uridine
Chemical data
Formula C18H27N5O21P4 
Mol. mass 773.32 g/mol
SMILES eMolecules & PubChem
 YesY(what is this?)  (verify)

Denufosol (INN) is an inhalable drug for the treatment of cystic fibrosis, being developed by Inspire Pharmaceuticals and sponsored by the Cystic Fibrosis Foundation. It has been tested in a number of Phase III clinical trials, initially with good outcomes,[1] but ultimately showing non-significant results compared with placebo.[2]

The drug was also investigated for the treatment of retinal detachment and other retinal diseases, but trials were terminated in 2006.[3]

Contents

Application

The substance was applied three times a day with an inhaler ("jet nebulizer"). To be effective, it had to reach the deeper parts of the lung (bronchioles), making it unsuitable for litte children under about five years of age.[4]

Mechanism of action

Cystic fibrosis is characterised by a defect of the chloride channel CFTR (cystic fibrosis transmembrane conductance regulator) on epithelial cells in the lungs. This channel is necessary to regulate the components of sweat, digestive juices, and mucus. Defects lead to a viscous, dehydrated mucus, hindering mucociliary clearance. Denufosol is an agonist at the P2Y2 subtype of purinergic receptors, opening an alternative chloride channel and so partly compensating the effects caused by the non-working CFTR.[5]

Chemistry

Denufosol consists of two nucleosides (composed of a nucleobase and a sugar each), 2'-desoxycytidine and uridine, linked by four units of phosphoric acid. It is used in form of its tetrasodium salt.

References

  1. ^ Accurso, F. J.; Moss, R. B.; Wilmott, R. W.; Anbar, R. D.; Schaberg, A. E.; Durham, T. A.; Ramsey, B. W.; the TIGER-1 Investigator Study Group (2010). "Denufosol Tetrasodium in Patients with Cystic Fibrosis and Normal to Mildly Impaired Lung Function". American Journal of Respiratory and Critical Care Medicine 183 (5): 627–634. doi:10.1164/rccm.201008-1267OC. PMID 21169471.  edit
  2. ^ Inspire Announces Results of Second Phase 3 Trial with Denufosol for Cystic Fibrosis
  3. ^ ClinicalTrials.gov NCT00083967 Study of Denufosol (INS37217) in Subjects With Rhegmatogenous Retinal Detachment
  4. ^ H. Spreitzer (14 March 2011). "Neue Wirkstoffe – Denufosol" (in German). Österreichische Apothekerzeitung (6/2011): 10. 
  5. ^ Kellerman, D.; Rossi Mospan, A.; Engels, J.; Schaberg, A.; Gorden, J.; Smiley, L. (2008). "Denufosol: A review of studies with inhaled P2Y2 agonists that led to Phase 3". Pulmonary Pharmacology & Therapeutics 21 (4): 600–607. doi:10.1016/j.pupt.2007.12.003. PMID 18276176.  edit


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