地纽福索四钠(Denufosol Tetrasodium) - 药物靶点：P2Y2 receptor_专利_临床

概要

基本信息

药物类型

小分子化药

别名

Denufosol、Denufosol tetrasodium (USAN)、INS 37217 ophthalmic

+ [3]

靶点

P2Y2 receptor

作用机制

P2Y2 receptor激动剂(嘌呤受体P2Y2激动剂)

治疗领域

免疫系统疾病感染遗传病与畸形+ [5]

在研适应症-

非在研适应症

囊性纤维化干眼综合征黄斑水肿+ [7]

原研机构

Merck Sharp & Dohme Corp.

在研机构-

非在研机构

Merck Sharp & Dohme Corp.

Inspire Pharmaceuticals, Inc.

最高研发阶段终止临床3期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构

分子式C18H27N5Na4O21P4

InChIKeyUJXLEAFWHDAVEO-WMUGRWSXSA-N

CAS号318250-11-2

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关联

15

项与地纽福索四钠相关的临床试验

NCT01181622 / Completed临床2期

A Phase 2, Multi-Center, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, 7-Day Safety and Tolerability Study of Denufosol Tetrasodium Inhalation Solution Administered Via PARI LC® Star in Patients 2 to 4 Years of Age With Cystic Fibrosis

The purpose of this study is to evaluate the safety and tolerability of denufosol 60 mg TID in pediatric CF patients 2 to 4 years of age

开始日期2010-08-01

申办/合作机构

Merck Sharp & Dohme Corp.

NCT00846781 / Terminated临床3期

Study 08-114 Open-label Extension of Study 08-110 - A Multi-Center Study of Denufosol Tetrasodium Inhalation Solution in Patients With Cystic Fibrosis Lung Disease (P08642) (DEFY)

The purpose of this study is to obtain data on the potential of long-term treatment with denufosol to improve the clinical course of CF lung disease in patients with mildly impaired lung function and to provide CF patients who completed study 08-110 continued access to denufosol.

开始日期2009-02-01

申办/合作机构

Merck Sharp & Dohme Corp.

NCT00625612 / Completed临床3期

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.

开始日期2008-02-01

申办/合作机构

Merck Sharp & Dohme Corp.

100 项与地纽福索四钠相关的临床结果

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100 项与地纽福索四钠相关的转化医学

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100 项与地纽福索四钠相关的专利（医药）

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30

项与地纽福索四钠相关的文献（医药）

2022-10-01·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

作者: 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.

2020-12-29·ACS Omega3区 · 化学

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

3区 · 化学

ArticleOA

作者: 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.

2013-04-01·The Journal of Pediatrics2区 · 医学

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

2区 · 医学

Article

作者: 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 项与地纽福索四钠相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D03685	地纽福索四钠	-	DB04983

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
肺囊性纤维化	临床3期	-	Merck Sharp & Dohme Corp.	2006-07-01
囊性纤维化	临床3期	新西兰	Inspire Pharmaceuticals, Inc.	-
囊性纤维化	临床3期	美国	Inspire Pharmaceuticals, Inc.	-
囊性纤维化	临床3期	澳大利亚	Inspire Pharmaceuticals, Inc.	-
囊性纤维化	临床3期	加拿大	Inspire Pharmaceuticals, Inc.	-
干眼综合征	临床3期	美国	-	-
视网膜水肿	临床3期	美国	-	-
常年性变应性鼻炎	临床3期	美国	-	-
常年性变应性鼻炎	临床3期	美国	-	-
鼻窦炎	临床3期	美国	-	-

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT00625612 (Pubmed \| J Cyst Fibros)	临床3期	囊性纤维化	466	Denufosol	(壓蓋淵衊網淵糧繭膚廠) = 顧廠鹽鏇襯膚鹽製觸齋獵襯選夢製齋鏇餘鑰衊 (鏇積鏇蓋製觸簾糧淵繭 ) 更多	不佳	2012-12-01
				Placebo	(壓蓋淵衊網淵糧繭膚廠) = 糧獵餘壓選憲淵願齋積獵襯選夢製齋鏇餘鑰衊 (鏇積鏇蓋製觸簾糧淵繭 ) 更多
NCT00357279 (Pubmed \| Pediatrics)	临床3期	肺囊性纤维化	352	Denufosol	(積夢蓋積壓窪窪遞廠鏇) = 醖齋選窪糧願選製艱憲製衊觸憲憲構觸齋觸窪 (繭窪願鹹膚襯鏇窪獵膚 )	积极	2011-03-01
				Placebo	(積夢蓋積壓窪窪遞廠鏇) = 廠獵簾製膚鏇選壓餘簾製衊觸憲憲構觸齋觸窪 (繭窪願鹹膚襯鏇窪獵膚 )