Study of degradation behaviour of montelukast sodium and its marketed formulation in oxidative and accelerated test conditions and prediction of physicochemical and ADMET properties of its degradation products using ADMET Predictor™

Tiwari, Shobhit Kumar; Singh, Dilip Kumar; Ladumor, Mayur K.; Chakraborti, Asit K.; Singh, Saranjit

doi:10.1016/j.jpba.2018.05.040

Cited by 22 publications

(14 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The results of two ghost peaks under different stress conditions were presented in Figure 4. The drug solution was stable under acidic Note: The 1 H and 13 C NMR data of OLM show similar signals in CDCl 3 (Table 3) and in DMSO. 6 Abbreviation: OLM, olmesartan medoxomil.…”

Section: Analysis Of Stress Studiesmentioning

confidence: 81%

“…Based on the combined analysis of 1 H, 13 C, HSQC, 1 H-1 H COSY, and HMBC spectra, all protons and carbon signals were assigned (Table 3) and the planar carbon chain structure of the entire molecule was proven. The 1 H-NMR data of ghost peak II showed seven distinct 1 H peaks in the aromatic region, instead of the six peaks for the drug.…”

Section: Mechanism-based Studymentioning

confidence: 99%

“…In order to reveal the formation and mechanism of the ghost peaks, a study outlined in Section 2.10 was performed. According to the literature, generation of radicals by Fe (II) and Fe (III) species has been extensively investigated [8][9][10][11][12] ; the radical scavengers were always used in stress studies to confirm the involvement of the radical pathway, 13,14 among which the mannitol and SOD were used to protect against oxidation by hydroxyl radical 15 and superoxide radical, 16 respectively. In this study, a significant decrease in the formation of ghost peaks I and II was observed in the presence of mannitol and SOD (Table 4).…”

Section: Formation Mechanism Of Ghost Peaksmentioning

confidence: 99%

See 2 more Smart Citations

“Ghost peaks” of olmesartan medoxomil: Two solution degradation products of olmesartan medoxomil via oxidation mediated by metal ions

et al. 2022

View full text Add to dashboard Cite

Two unknown solution degradants were found during the dissolution testing in 0.1-M HCl for olmesartan medoxomil (OLM) tablets. The structure of the degradants was identified and characterized by liquid chromatography-ultraviolet (LC-UV), liquid chromatography with tandem mass spectrometry (LC-MS/MS), and nuclear magnetic resonance (NMR) and demonstrated to be cyclization of tetrazole and benzene in the olmesartan (OL) and OLM structures. A series of studies including stress studies, simulation studies, and mechanism-based studies were performed to reveal the potential mechanisms that lead to the formation of the unknown degradants. The study results demonstrated that the degradation was catalyzed with radicals that originated from the metal ions leached from the inner surface of high-performance liquid chromatography (HPLC) glass vials with dissolved oxygen under acidic condition. Prerinsing the glass vials with acidic solution dissolved with EDTA can effectively avoid the generation of such oxidative impurities. The present work provides new insights into the understanding of degradation pathways of OLM, which might support the development of OLM tablets.

show abstract

Section: Analysis Of Stress Studiesmentioning

confidence: 81%

Section: Mechanism-based Studymentioning

confidence: 99%

Section: Formation Mechanism Of Ghost Peaksmentioning

confidence: 99%

See 1 more Smart Citation

“Ghost peaks” of olmesartan medoxomil: Two solution degradation products of olmesartan medoxomil via oxidation mediated by metal ions

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Within the compound-specific information section, there is compound identification data including the assigned UNC number, associated lot ID, an alternative (common) name, CAS number, vendor that provided the solid sample, SMILES string, and designation as a positive control (where applicable). Also within this subsection is data related to predicted BBB penetration by the StarDrop software program (log([brain]:[blood])) [25][26][27][28] as well as by the ADMET Predictor software program [29][30][31]: qualitative likelihood of crossing BBB and logarithm of the brain/blood partition coefficient (LogBB). Other predicted compound properties included from the ADMET Predictor software program are whether the compound is a likely P-glycoprotein (P-gp) and/or breast cancer resistance protein (BCRP) substrate and/or inhibitor, making it susceptible to efflux.…”

Section: Resultsmentioning

confidence: 99%

AD Informer Set: Chemical tools to facilitate Alzheimer’s disease drug discovery

Potjewyd

Annor-Gyamfi

Aubé³

et al. 2021

Preprint

View full text Add to dashboard Cite

Introduction: The portfolio of novel targets to treat Alzheimer's disease (AD) has been enriched by the AMP-AD program. Methods: A cheminformatics-driven effort enabled identification of existing small molecule modulators for many protein targets nominated by AMP-AD and suitable positive control compounds to be included in the set. Results: We have built an annotated set of 171 small molecule modulators, including mostly inhibitors, targeting 98 unique proteins that have been nominated by AMP-AD consortium members as novel targets for AD treatment. These small molecules vary in their quality and should be considered chemical tools that can be used in efforts to validate therapeutic hypotheses, but which would require further optimization. A physical copy of the AD Informer Set can be ordered via the AD Knowledge Portal. Discussion: Small molecule tools that enable target validation are important tools for the translation of novel hypotheses into viable therapeutic strategies for AD.

show abstract

“…S12). Because of a lack of information about the metabolic pathways for phenoxybenzamine, the ADMET Predictor was employed to investigate the metabolic enzymes, with the results showing that the relevant enzymes such as CYP1A2 are similarly highly expressed in PXB cells 31 . Of course, from these expression data we can analyse only correlations,further studies are necessary to identify the cause of the different phenotype of phenoxybenzamine treatment from the viewpoint of exposure.…”

Section: Discussionmentioning

confidence: 99%

Decomposition profile data analysis of multiple drug effects identifies endoplasmic reticulum stress-inducing ability as an unrecognized factor

Morita

Mizuno

Kusuhara

2020

Sci Rep

View full text Add to dashboard Cite

Chemicals have multiple effects in biological systems. Because their on-target effects dominate the output, their off-target effects are often overlooked and can sometimes cause dangerous adverse events. Recently, we developed a novel decomposition profile data analysis method, orthogonal linear separation analysis (OLSA), to analyse multiple effects. In this study, we tested whether OLSA identified the ability of drugs to induce endoplasmic reticulum (ER) stress as a previously unrecognized factor. After analysing the transcriptome profiles of MCF7 cells treated with different chemicals, we focused on a vector characterized by well-known ER stress inducers, such as ciclosporin A. We selected five drugs predicted to be unrecognized ER stress inducers, based on their inducing ability scores derived from OLSA. These drugs actually induced X-box binding protein 1 splicing, an indicator of ER stress, in MCF7 cells in a concentration-dependent manner. Two structurally different representatives of the five test compounds exhibited similar results in HepG2 and HuH7 cells, but not in PXB primary hepatocytes derived from human-liver chimeric mice. These results indicate that our decomposition strategy using OLSA uncovered the ER stress-inducing ability of drugs as an unrecognized effect, the manifestation of which depended on the background of the cells. Small compounds have the capacity to interact with multiple cellular proteins, thereby mediating multiple effects depending on their exposure to interacting proteins. It is quite difficult to identify the full range of effects of a new chemical, even for its developers, and some factors may be unrecognized. Even approved drugs show off-target effects that are often unrecognized during drug development, and which can lead to adverse reactions including lethal effects. For instance, astemizole has been withdrawn from the market in most countries because it causes a fatal side effect, cardiac arrhythmia 1,2 , by blocking the human Ether-ago go Related Gene potassium channel, thereby causing QT interval prolongation and torsade de pointes. However, we should not be too negative about unrecognized effects of small compounds, because identification of these can lead to drug repurposing. For example, memantine was synthesized in 1968 as a derivative of amantadine, an anti-influenza agent. Recently, it was revealed that this anti-influenza agent is also an antagonist for the N-methyl-D-aspartate receptor, and the drug has become a medication for dementia 3. Thus, the important question is how such unrecognized effects of chemicals can be identified. Profile data analysis is quite useful in addressing this issue. Although the terminology sometimes varies between contexts, the method is a type of multivariate analysis that describes data using multiple variables and investigates the relationship between data with high robustness and detection power by sharing information about the structure of the data 4. Data from "omics" analysis, which converts biological information of a specim...

show abstract

Study of degradation behaviour of montelukast sodium and its marketed formulation in oxidative and accelerated test conditions and prediction of physicochemical and ADMET properties of its degradation products using ADMET Predictor™

Cited by 22 publications

References 39 publications

“Ghost peaks” of olmesartan medoxomil: Two solution degradation products of olmesartan medoxomil via oxidation mediated by metal ions

“Ghost peaks” of olmesartan medoxomil: Two solution degradation products of olmesartan medoxomil via oxidation mediated by metal ions

AD Informer Set: Chemical tools to facilitate Alzheimer’s disease drug discovery

Decomposition profile data analysis of multiple drug effects identifies endoplasmic reticulum stress-inducing ability as an unrecognized factor

Contact Info

Product

Resources

About