Delving into the Latest Updates on Denufosol Tetrasodium with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Denufosol, Denufosol tetrasodium (USAN), INS 37217 ophthalmic

+ [3]

Target

P2Y2 receptor

Mechanism

P2Y2 receptor agonists(Purinergic receptor P2Y2 agonists)

Therapeutic Areas

Immune System DiseasesInfectious DiseasesCongenital Disorders+ [5]

Active Indication-

Inactive Indication

Cystic FibrosisDry Eye SyndromesMacular Edema+ [7]

Originator Organization

Merck Sharp & Dohme Corp.

Active Organization-

Inactive Organization

Merck Sharp & Dohme Corp.

Inspire Pharmaceuticals, Inc.

Drug Highest PhaseDiscontinuedPhase 3

First Approval Date-

Regulation-

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Structure

Molecular FormulaC18H27N5Na4O21P4

InChIKeyUJXLEAFWHDAVEO-WMUGRWSXSA-N

CAS Registry318250-11-2

View All Structures (2)

A Phase 3, International, Multi-Center, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Efficacy and Safety Study of Denufosol Tetrasodium Inhalation Solution in Patients With Cystic Fibrosis Lung Disease and FEV1 Greater Than or Equal to 75% Predicted But Less Than or Equal to 110% Predicted

The purpose of this trial is to evaluate the safety and effectiveness of one dose strength of Denufosol compared to placebo in patients with CF and a predicted FEV1 of greater than or equal to 75% but less than or equal to 110% predicted.

Start Date01 Feb 2008

Sponsor / Collaborator

Merck Sharp & Dohme Corp.

100 Clinical Results associated with Denufosol Tetrasodium

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100 Translational Medicine associated with Denufosol Tetrasodium

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100 Patents (Medical) associated with Denufosol Tetrasodium

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30

Literatures (Medical) associated with Denufosol Tetrasodium

01 Oct 2022·Structural Chemistry

Drug repurposing against main protease and RNA-dependent RNA polymerase of SARS-CoV-2 using molecular docking, MM-GBSA calculations and molecular dynamics

Article

Author: Mohammed, Ahmed O ; Makki, Alaa A ; Alzain, Abdulrahim A ; Ibraheem, Walaa ; Abo-Idrees, Mazin I

A virus called severe acute respiratory distress syndrome coronavirus type 2 (SARS-CoV-2) is the causing organism of coronavirus disease 2019 (COVID-19), which has severely affected human life and threatened public health. The pandemic took millions of lives worldwide and caused serious negative effects on human society and the economy. SARS-CoV-2 main protease (Mpro) and RNA-dependent RNA polymerase (RdRp) are interesting targets due to their crucial role in viral replication and growth. Since there is only one approved therapy for COVID-19, drug repurposing is a promising approach to finding molecules with potential activity against COVID-19 in a short time and at minimal cost. In this study, virtual screening was performed on the ChEMBL library containing 9923 FDA-approved drugs, using various docking filters with different accuracy. The best drugs with the highest docking scores were further examined for molecular dynamics (MD) studies and MM-GBSA calculations. The results of this study suggest that nadide, cangrelor and denufosol are promising potential candidates against COVID-19. Further in vitro, preclinical and clinical studies of these candidates would help to discover safe and effective anti-COVID-19 drugs.

29 Dec 2020·ACS OmegaQ3 · CHEMISTRY

Structure-Based Virtual Screening and Biochemical Validation to Discover a Potential Inhibitor of the SARS-CoV-2 Main Protease

Q3 · CHEMISTRY

ArticleOA

Author: Pant, Pradeep ; Vikram, Naval ; Rani, Chitra ; Sharma, Pradeep ; Vijayan, Viswanathan ; Gupta, Akshita ; Sharma, Sujata ; Singh, Tej Pal ; Kaur, Punit

The recent pandemic caused by SARS-CoV-2 has led the world to a standstill, causing a medical and economic crisis worldwide. This crisis has triggered an urgent need to discover a possible treatment strategy against this novel virus using already-approved drugs. The main protease (Mpro) of this virus plays a critical role in cleaving the translated polypeptides that makes it a potential drug target against COVID-19. Taking advantage of the recently discovered three-dimensional structure of Mpro, we screened approved drugs from the Drug Bank to find a possible inhibitor against Mpro using computational methods and further validating them with biochemical studies. The docking and molecular dynamics study revealed that DB04983 (denufosol) showed the best glide docking score, -11.884 kcal/mol, and MM-PBSA binding free energy, -10.96 kcal/mol. Cobicistat, cangrelor (previous computational studies in our lab), and denufosol (current study) were tested for the in vitro inhibitory effects on Mpro. The IC₅₀ values of these drugs were ∼6.7 μM, 0.9 mM, and 1.3 mM, respectively, while the values of dissociation constants calculated using surface plasmon resonance were ∼2.1 μM, 0.7 mM, and 1.4 mM, respectively. We found that cobicistat is the most efficient inhibitor of Mpro both in silico and in vitro. In conclusion, cobicistat, which is already an FDA-approved drug being used against HIV, may serve as a good inhibitor against the main protease of SARS-CoV-2 that, in turn, can help in combating COVID-19, and these results can also form the basis for the rational structure-based drug design against COVID-19.

01 Apr 2013·The Journal of PediatricsQ2 · MEDICINE

Pitfalls of Drug Development: Lessons Learned from Trials of Denufosol in Cystic Fibrosis

Q2 · MEDICINE

Article

Author: Moss, Richard B

T he life-shortening genetic disease cystic fibrosis (CF) is caused by mutations in the CF gene on both alleles, resulting in failure of a defective CF transmembrane conductance regulator (CFTR) glycoprotein to normally regulate chloride and bicarbonate flux at the airway surface. According to a leading theory of CF pathogenesis, the “volume depletion” hypothesis, this abnormal anion transport leads to reduced airway surface liquid, airway dehydration, and impairedmucociliary clearance, resulting in vulnerability to airway obstruction, microbial infection, and inflammation. In 1991, investigators at the University of North Carolina discovered that triphosphate nucleotides, such as adenosine5’-triphosphate and uridine-5’-triphosphate, stimulated chloride secretion in both normal and CF respiratory epithelia, offering a potential bypass mechanism for defective CFTR. Triphosphate nucleotides transduce a signal by binding to purinergic receptors on respiratory epithelial cells specifically responding to purine and pyrimidine nucleotides, termed P2Y2 receptors. This leads to release of intracellular calcium and activates calcium-dependent chloride channels (CaCCs) distinct from CFTR. In vitro tissue culture studies have confirmed that adenosine-5’-triphosphate and uridine5’-triphosphate can restore liquid transport in CF cultures within a few minutes, enhance tracheal mucus velocity in sheep models, and acutely increase sputum volume and mucociliary clearance in smokers. Additional actions of P2Y2 agonists also have been reported from cell culture experiments, including stimulation of ciliary beat frequency, increased mucin secretion from goblet cells and surfactant from type II alveolar cells, and inhibition of epithelial sodium absorption, the net sum of these plausibly resulting in improved airway hydration and increased mucociliary transport that should be beneficial in treating CF. Native triphosphate nucleotides are rapidly metabolized by ectonucleotidases in an autocrine/paracrine manner, however. This has led to the development of dinucleotides, INS365 and INS37217, that are more resistant to enzymatic degradation as assessed in 2 preclinical models: ex vivo exposure of the nucelotides to CF sputum samples and in vitro addition to human nasal ciliated epithelial cell cultures. In these models, these dinucleotides had sufficient stability to merit consideration for drug development, with INS37217 (later named denufosol) outperforming INS365. Denufosol’s

100 Deals associated with Denufosol Tetrasodium

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External Link

KEGG	Wiki	ATC	Drug Bank
D03685	Denufosol Tetrasodium	-	DB04983

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Pulmonary Cystic Fibrosis	Phase 3	-	Merck Sharp & Dohme Corp.	01 Jul 2006
Cystic Fibrosis	Phase 3	AU	Inspire Pharmaceuticals, Inc.	-
Cystic Fibrosis	Phase 3	CA	Inspire Pharmaceuticals, Inc.	-
Cystic Fibrosis	Phase 3	US	Inspire Pharmaceuticals, Inc.	-
Cystic Fibrosis	Phase 3	NZ	Inspire Pharmaceuticals, Inc.	-
Dry Eye Syndromes	Phase 3	US	-	-
Retinal oedema	Phase 3	US	-	-
Rhinitis, Allergic, Perennial	Phase 3	US	-	-
Sinusitis	Phase 3	US	-	-
Rhinitis, Allergic, Perennial	Phase 2	US	-	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT00625612 (Pubmed \| J Cyst Fibros)	Phase 3	Cystic Fibrosis	466	Denufosol	(oasgvfueeg) = mnnappdydv wnbsupyktv (ctyxsutkak ) View more	Negative	01 Dec 2012
				Placebo	(oasgvfueeg) = sxbonnnjxz wnbsupyktv (ctyxsutkak ) View more
NCT00357279 (Pubmed \| Pediatrics)	Phase 3	Pulmonary Cystic Fibrosis	352	Denufosol	(xnrcphtkru) = wxobkicbge voqtpbxwfu (ekzdouhpwp )	Positive	01 Mar 2011
				Placebo	(xnrcphtkru) = vugwszptdp voqtpbxwfu (ekzdouhpwp )