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Denufosol
Clinical data
Other names	INS37217; 2'-Desoxycytidine (5')tetraphospho(5')uridine
Routes of; administration	Inhalation
ATC code	none;
Legal status
Legal status	Investigational;
Identifiers
	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;
CAS Number	211448-85-0 ;
PubChem CID	9875516;
ChemSpider	8051201;
UNII	5PC250KSSH;
ChEMBL	ChEMBL1767407;
CompTox Dashboard (EPA)	DTXSID50870235 ;
Chemical and physical data
Formula	C18H27N5O21P4
Molar mass	773.323 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES C1[C@@H]([C@H](O[C@H]1N2C=CC(=NC2=O)N)COP(=O)(O)OP(=O)(O)OP(=O)(O)OP(=O)(O)OC[C@@H]3[C@H]([C@H]([C@@H](O3)N4C=CC(=O)NC4=O)O)O)O;
	InChI InChI=1S/C18H27N5O21P4/c19-11-1-3-22(17(28)20-11)13-5-8(24)9(40-13)6-38-45(30,31)42-47(34,35)44-48(36,37)43-46(32,33)39-7-10-14(26)15(27)16(41-10)23-4-2-12(25)21-18(23)29/h1-4,8-10,13-16,24,26-27H,5-7H2,(H,30,31)(H,32,33)(H,34,35)(H,36,37)(H2,19,20,28)(H,21,25,29)/t8-,9+,10+,13+,14+,15+,16+/m0/s1; Key:FPNPSEMJLALQSA-MIYUEGBISA-N;
	(verify)

Denufosol (INN) is an inhaled drug for the treatment of cystic fibrosis, being developed by Inspire Pharmaceuticals and sponsored by the Cystic Fibrosis Foundation. It was tested in two Phase III clinical trials, TIGER-1 and TIGER-2. Initially, in the first Phase III trial, TIGER-1, the compound showed significant results as compared with placebo.^[1] In the second Phase III trial, TIGER-2, the compound did not meet the primary endpoint, a significant change in baseline FEV1 (forced expiratory volume in one second) at the week 48 endpoint as compared to placebo.^[2] As of 2011, no additional clinical studies are being conducted with the compound.

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

Application

In Phase III studies, denufosol was orally inhaled by patients with cystic fibrosis three times a day using a jet nebulizer. To be effective, it had to reach the deeper parts of the lung (bronchioles), making it unsuitable for children under 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. The CFTR regulates 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 which via its associated G protein leads to activation of alternative chloride channel. Activating this alternate chloride channel theoretically increases ion transport in cystic fibrosis patients which compensates the effects caused by the non-functioning CFTR.^[5]

Chemistry

Denufosol consists of two nucleosides (composed of a nucleobase and a sugar each), deoxycytidine and uridine, linked on their sugars by four units of phosphoric acid. It is used in form of its tetrasodium salt.^{[citation needed]}

References

^ Accurso FJ, Moss RB, Wilmott RW, Anbar RD, Schaberg AE, Durham TA, Ramsey BW (March 2011). "Denufosol tetrasodium in patients with cystic fibrosis and normal to mildly impaired lung function". American Journal of Respiratory and Critical Care Medicine. 183 (5): 627–34. doi:10.1164/rccm.201008-1267OC. PMID 21169471.
^ "Inspire Announces Results of Second Phase 3 Trial with Denufosol for Cystic Fibrosis". Archived from the original on 2012-03-22. Retrieved 2011-04-03.
^ Clinical trial number NCT00083967 for "Study of Denufosol (INS37217) in Subjects With Rhegmatogenous Retinal Detachment" at ClinicalTrials.gov
^ Spreitzer H (14 March 2011). "Neue Wirkstoffe – Denufosol". Österreichische Apothekerzeitung (in German) (6/2011): 10.
^ Kellerman D, Rossi Mospan A, Engels J, Schaberg A, Gorden J, Smiley L (August 2008). "Denufosol: a review of studies with inhaled P2Y(2) agonists that led to Phase 3". Pulmonary Pharmacology & Therapeutics. 21 (4): 600–7. doi:10.1016/j.pupt.2007.12.003. PMID 18276176.

[1] Accurso FJ, Moss RB, Wilmott RW, Anbar RD, Schaberg AE, Durham TA, Ramsey BW (March 2011). "Denufosol tetrasodium in patients with cystic fibrosis and normal to mildly impaired lung function". American Journal of Respiratory and Critical Care Medicine. 183 (5): 627–34. doi:10.1164/rccm.201008-1267OC. PMID 21169471.

[2] "Inspire Announces Results of Second Phase 3 Trial with Denufosol for Cystic Fibrosis". Archived from the original on 2012-03-22. Retrieved 2011-04-03.

[3] Clinical trial number NCT00083967 for "Study of Denufosol (INS37217) in Subjects With Rhegmatogenous Retinal Detachment" at ClinicalTrials.gov

[Spreitzer-4] Spreitzer H (14 March 2011). "Neue Wirkstoffe – Denufosol". Österreichische Apothekerzeitung (in German) (6/2011): 10.

[5] Kellerman D, Rossi Mospan A, Engels J, Schaberg A, Gorden J, Smiley L (August 2008). "Denufosol: a review of studies with inhaled P2Y(2) agonists that led to Phase 3". Pulmonary Pharmacology & Therapeutics. 21 (4): 600–7. doi:10.1016/j.pupt.2007.12.003. PMID 18276176.

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