Denufosol
Identification
- Generic Name
- Denufosol
- DrugBank Accession Number
- DB04983
- Background
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.
- Type
- Small Molecule
- Groups
- Investigational
- Structure
- Weight
- Average: 773.323
Monoisotopic: 773.014900901 - Chemical Formula
- C18H27N5O21P4
- Synonyms
- Denufosol
Pharmacology
- Indication
For use as an inhaled treatment for cystic fibrosis.
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- 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.
Target Actions Organism UP2Y purinoceptor 2 Not Available Humans - 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
- Adverse Effects
- Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.
- Toxicity
Not Available
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.Not Available
- Food Interactions
- Not Available
Products
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- Product Ingredients
Ingredient UNII CAS InChI Key Denufosol tetrasodium 82M942WZ4A 318250-11-2 PASYJVRFGUDDEW-WMUGRWSXSA-J
Categories
- Drug Categories
- Chemical TaxonomyProvided by Classyfire
- 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 / Alcohol / Alkyl phosphate / Amine / Aminopyrimidine / Aromatic heteromonocyclic compound / Azacycle / Glycosyl compound / Heteroaromatic compound / Hydrocarbon derivative show 28 more
- Molecular Framework
- Aromatic heteromonocyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 5PC250KSSH
- CAS number
- 211448-85-0
- 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
References
- General References
- 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. [Article]
- 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. [Article]
- 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. [Article]
- 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. [Article]
- External Links
- KEGG Drug
- D03685
- PubChem Compound
- 9875516
- PubChem Substance
- 175426926
- ChemSpider
- 8051201
- BindingDB
- 50270553
- ChEMBL
- CHEMBL507282
- ZINC
- ZINC000085540154
- Wikipedia
- Denufosol
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 3 Completed Treatment Cystic Fibrosis (CF) 2 3 Terminated Treatment Cystic Fibrosis (CF) 1 2 Completed Treatment Cystic Fibrosis (CF) 4 2 Completed Treatment Perennial Allergic Rhinitis (PAR) 1 2 Terminated Treatment Cystic Fibrosis (CF) 1
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
Property Value Source Water Solubility 22.3 mg/mL ALOGPS logP 0.19 ALOGPS logP -5.4 Chemaxon logS -1.5 ALOGPS pKa (Strongest Acidic) 0.76 Chemaxon pKa (Strongest Basic) 0.13 Chemaxon Physiological Charge -4 Chemaxon Hydrogen Acceptor Count 18 Chemaxon Hydrogen Donor Count 9 Chemaxon Polar Surface Area 382.6 Å2 Chemaxon Rotatable Bond Count 14 Chemaxon Refractivity 145.31 m3·mol-1 Chemaxon Polarizability 60.36 Å3 Chemaxon Number of Rings 4 Chemaxon Bioavailability 0 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption - 0.7448 Blood Brain Barrier + 0.6534 Caco-2 permeable - 0.7129 P-glycoprotein substrate Non-substrate 0.5565 P-glycoprotein inhibitor I Non-inhibitor 0.7768 P-glycoprotein inhibitor II Non-inhibitor 0.9588 Renal organic cation transporter Non-inhibitor 0.9246 CYP450 2C9 substrate Non-substrate 0.7747 CYP450 2D6 substrate Non-substrate 0.8387 CYP450 3A4 substrate Substrate 0.5252 CYP450 1A2 substrate Non-inhibitor 0.9041 CYP450 2C9 inhibitor Non-inhibitor 0.8808 CYP450 2D6 inhibitor Non-inhibitor 0.8965 CYP450 2C19 inhibitor Non-inhibitor 0.8701 CYP450 3A4 inhibitor Non-inhibitor 0.7567 CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9338 Ames test Non AMES toxic 0.6808 Carcinogenicity Non-carcinogens 0.8416 Biodegradation Not ready biodegradable 0.9659 Rat acute toxicity 2.4198 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.9427 hERG inhibition (predictor II) Non-inhibitor 0.5444
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 175.6311 predictedDeepCCS 1.0 (2019) [M+H]+ 177.57375 predictedDeepCCS 1.0 (2019) [M+Na]+ 184.60612 predictedDeepCCS 1.0 (2019)
Targets
- 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
- 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. [Article]
- 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. [Article]
- 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. [Article]
- 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. [Article]
- 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. [Article]
- Brunschweiger A, Muller CE: P2 receptors activated by uracil nucleotides--an update. Curr Med Chem. 2006;13(3):289-312. [Article]
- 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. [Article]
Drug created at October 21, 2007 22:23 / Updated at February 02, 2024 22:51