Denufosol

Identification

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Name
Denufosol
Accession Number
DB04983
Type
Small Molecule
Groups
Investigational
Description

Denufosol was an inhaled drug used for the treatment of cystic fibrosis (CF), showing various improvements in lung function during a phase III clinical trial. A new drug application (NDA) was filed with the FDA in 2011, however, the second phase III clinical trial showed a lack of improvement in lung function for cystic fibrosis patients taking denufosol. The drug was also evaluated in the treatment of retinal detachment and other diseases of the retina. Denufosol has not gained FDA approval, and clinical trials with this drug have ceased since 2011.

Structure
Thumb
Synonyms
Not Available
Product Ingredients
IngredientUNIICASInChI Key
Denufosol tetrasodium82M942WZ4A318250-11-2PASYJVRFGUDDEW-WMUGRWSXSA-J
Categories
UNII
5PC250KSSH
CAS number
211448-85-0
Weight
Average: 773.323
Monoisotopic: 773.014900901
Chemical Formula
C18H27N5O21P4
InChI Key
FPNPSEMJLALQSA-MIYUEGBISA-N
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
IUPAC Name
[({[(2R,3S,5R)-5-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-3-hydroxyoxolan-2-yl]methoxy}(hydroxy)phosphoryl)oxy]({[({[(2R,3S,4R,5R)-5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy}(hydroxy)phosphoryl)oxy](hydroxy)phosphoryl}oxy)phosphinic acid
SMILES
[H]N([H])C1=NC(=O)N(C=C1)[C@H]1C[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)N2C=CC(=O)N([H])C2=O)O1

Pharmacology

Indication

For use as an inhaled treatment for cystic fibrosis.

Pharmacodynamics

Denufosol is designed to enhance the lung's innate mucosal hydration and mucociliary clearance through stimulation of the P2Y2 receptor. The pharmacologic profile of denufosol parallels that of UTP, leading to increased chloride and water secretion, increased cilia beat frequency, and increased mucin release.

Mechanism of action

Denufosol tetrasodium is a selective P2Y2 agonist designed to enhance the lung's innate mucosal hydration and mucociliary clearance mechanisms by activating an alternative ion channel that acts in the same way as the defective ion channel in moving salt and water to the surface of the airways. Based on pre-clinical and clinical work, denufosol has several pharmacological actions contributing to its mechanism of action: hydration of the airways by stimulating chloride and liquid secretions on the epithelial cell surface; inhibition of epithelial sodium absorption; enhancement of ciliary beat frequency; and stimulation of mucin secretion. This unique mechanism of action represents a differentiated approach relative to other approved CF products and may be important in intervening in the early clinical course of CF lung disease.

TargetActionsOrganism
UP2Y purinoceptor 2Not AvailableHumans
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

General References
  1. Yerxa BR, Sabater JR, Davis CW, Stutts MJ, Lang-Furr M, Picher M, Jones AC, Cowlen M, Dougherty R, Boyer J, Abraham WM, Boucher RC: Pharmacology of INS37217 [P(1)-(uridine 5')-P(4)- (2'-deoxycytidine 5')tetraphosphate, tetrasodium salt], a next-generation P2Y(2) receptor agonist for the treatment of cystic fibrosis. J Pharmacol Exp Ther. 2002 Sep;302(3):871-80. [PubMed:12183642]
  2. Deterding RR, Lavange LM, Engels JM, Mathews DW, Coquillette SJ, Brody AS, Millard SP, Ramsey BW: Phase 2 randomized safety and efficacy trial of nebulized denufosol tetrasodium in cystic fibrosis. Am J Respir Crit Care Med. 2007 Aug 15;176(4):362-9. Epub 2007 Apr 19. [PubMed:17446337]
  3. Maminishkis A, Jalickee S, Blaug SA, Rymer J, Yerxa BR, Peterson WM, Miller SS: The P2Y(2) receptor agonist INS37217 stimulates RPE fluid transport in vitro and retinal reattachment in rat. Invest Ophthalmol Vis Sci. 2002 Nov;43(11):3555-66. [PubMed:12407168]
  4. Kellerman D, Evans R, Mathews D, Shaffer C: Inhaled P2Y2 receptor agonists as a treatment for patients with Cystic Fibrosis lung disease. Adv Drug Deliv Rev. 2002 Dec 5;54(11):1463-74. [PubMed:12458155]
External Links
KEGG Drug
D03685
PubChem Compound
9875516
PubChem Substance
175426926
ChemSpider
8051201
BindingDB
50270553
ChEMBL
CHEMBL507282
Wikipedia
Denufosol

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentHealthy Volunteers2
2CompletedTreatmentCystic Fibrosis (CF)3

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility22.3 mg/mLALOGPS
logP0.19ALOGPS
logP-5.4ChemAxon
logS-1.5ALOGPS
pKa (Strongest Acidic)0.76ChemAxon
pKa (Strongest Basic)0.13ChemAxon
Physiological Charge-4ChemAxon
Hydrogen Acceptor Count18ChemAxon
Hydrogen Donor Count9ChemAxon
Polar Surface Area382.6 Å2ChemAxon
Rotatable Bond Count14ChemAxon
Refractivity145.31 m3·mol-1ChemAxon
Polarizability60.36 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption-0.7448
Blood Brain Barrier+0.6534
Caco-2 permeable-0.7129
P-glycoprotein substrateNon-substrate0.5565
P-glycoprotein inhibitor INon-inhibitor0.7768
P-glycoprotein inhibitor IINon-inhibitor0.9588
Renal organic cation transporterNon-inhibitor0.9246
CYP450 2C9 substrateNon-substrate0.7747
CYP450 2D6 substrateNon-substrate0.8387
CYP450 3A4 substrateSubstrate0.5252
CYP450 1A2 substrateNon-inhibitor0.9041
CYP450 2C9 inhibitorNon-inhibitor0.8808
CYP450 2D6 inhibitorNon-inhibitor0.8965
CYP450 2C19 inhibitorNon-inhibitor0.8701
CYP450 3A4 inhibitorNon-inhibitor0.7567
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9338
Ames testNon AMES toxic0.6808
CarcinogenicityNon-carcinogens0.8416
BiodegradationNot ready biodegradable0.9659
Rat acute toxicity2.4198 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9427
hERG inhibition (predictor II)Non-inhibitor0.5444
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as (5'->5')-dinucleotides. These are dinucleotides where the two bases are connected via a (5'->5')-phosphodiester linkage.
Kingdom
Organic compounds
Super Class
Nucleosides, nucleotides, and analogues
Class
(5'->5')-dinucleotides
Sub Class
Not Available
Direct Parent
(5'->5')-dinucleotides
Alternative Parents
Pyrimidine ribonucleoside polyphosphates / Pyrimidine 2'-deoxyribonucleoside polyphosphates / Pentose phosphates / Glycosylamines / Monosaccharide phosphates / Aminopyrimidines and derivatives / Monoalkyl phosphates / Pyrimidones / Hydropyrimidines / Imidolactams
show 12 more
Substituents
(5'->5')-dinucleotide / Pyrimidine ribonucleoside polyphosphate / Pyrimidine 2'-deoxyribonucleoside polyphosphate / Pentose phosphate / Pentose-5-phosphate / Glycosyl compound / N-glycosyl compound / Monosaccharide phosphate / Aminopyrimidine / Pyrimidone
show 28 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Details
1. P2Y purinoceptor 2
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Utp-activated nucleotide receptor activity
Specific Function
Receptor for ATP and UTP coupled to G-proteins that activate a phosphatidylinositol-calcium second messenger system. The affinity range is UTP = ATP > ATP-gamma-S >> 2-methylthio-ATP = ADP.
Gene Name
P2RY2
Uniprot ID
P41231
Uniprot Name
P2Y purinoceptor 2
Molecular Weight
42272.92 Da
References
  1. Maminishkis A, Jalickee S, Blaug SA, Rymer J, Yerxa BR, Peterson WM, Miller SS: The P2Y(2) receptor agonist INS37217 stimulates RPE fluid transport in vitro and retinal reattachment in rat. Invest Ophthalmol Vis Sci. 2002 Nov;43(11):3555-66. [PubMed:12407168]
  2. Meyer CH, Hotta K, Peterson WM, Toth CA, Jaffe GJ: Effect of INS37217, a P2Y(2) receptor agonist, on experimental retinal detachment and electroretinogram in adult rabbits. Invest Ophthalmol Vis Sci. 2002 Nov;43(11):3567-74. [PubMed:12407169]
  3. Kellerman D, Evans R, Mathews D, Shaffer C: Inhaled P2Y2 receptor agonists as a treatment for patients with Cystic Fibrosis lung disease. Adv Drug Deliv Rev. 2002 Dec 5;54(11):1463-74. [PubMed:12458155]
  4. Nour M, Quiambao AB, Peterson WM, Al-Ubaidi MR, Naash MI: P2Y(2) receptor agonist INS37217 enhances functional recovery after detachment caused by subretinal injection in normal and rds mice. Invest Ophthalmol Vis Sci. 2003 Oct;44(10):4505-14. [PubMed:14507899]
  5. Deterding R, Retsch-Bogart G, Milgram L, Gibson R, Daines C, Zeitlin PL, Milla C, Marshall B, Lavange L, Engels J, Mathews D, Gorden J, Schaberg A, Williams J, Ramsey B: Safety and tolerability of denufosol tetrasodium inhalation solution, a novel P2Y2 receptor agonist: results of a phase 1/phase 2 multicenter study in mild to moderate cystic fibrosis. Pediatr Pulmonol. 2005 Apr;39(4):339-48. [PubMed:15704203]
  6. Brunschweiger A, Muller CE: P2 receptors activated by uracil nucleotides--an update. Curr Med Chem. 2006;13(3):289-312. [PubMed:16475938]
  7. Deterding RR, Lavange LM, Engels JM, Mathews DW, Coquillette SJ, Brody AS, Millard SP, Ramsey BW: Phase 2 randomized safety and efficacy trial of nebulized denufosol tetrasodium in cystic fibrosis. Am J Respir Crit Care Med. 2007 Aug 15;176(4):362-9. Epub 2007 Apr 19. [PubMed:17446337]

Drug created on October 21, 2007 16:23 / Updated on June 04, 2019 06:14