Novel rearrangements of an N-oxide degradate formed from oxidation of a morpholine acetal substance P antagonist

Zhao, Zhongxi; Qin, Xue-Zhi; Wu, Allen; Yuan, Yang

doi:10.1002/jps.20115

Cited by 9 publications

(4 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Monohydroxylation occurs mainly on position 2 of the morpholine group, which results in opening of the ring system. Hydroxylation on morpholino rings attached to heterocycles has been reported previously and N-oxidations have also been described (Langner et al, 1993;Baker et al, 1999;Huskey et al, 2004;Zhang et al, 2004;Zhao et al, 2004). Our study suggests that the modest bioavailability of NU7026 is not due to first pass metabolism as the relative proportion of administered dose present as parent or metabolites are similar after i.v., i.p.…”

Section: Discussionsupporting

confidence: 81%

Preclinical pharmacokinetics and metabolism of a novel prototype DNA-PK inhibitor NU7026

et al. 2005

View full text Add to dashboard Cite

In this study we investigated the in vitro time dependence of radiosensitisation, pharmacokinetics and metabolism of NU7026, a novel inhibitor of the DNA repair enzyme DNA-dependent protein kinase (DNA-PK). At a dose of 10 mM, which is nontoxic to cells per se, a minimum NU7026 exposure of 4 h in combination with 3 Gy radiation is required for a significant radiosensitisation effect in CH1 human ovarian cancer cells. Following intravenous administration to mice at 5 mg kg À1 , NU7026 underwent rapid plasma clearance (0.108 l h À1 ) and this was largely attributed to extensive metabolism. Bioavailability following interperitoneal (i.p.) and p.o. administration at 20 mg kg À1 was 20 and 15%, respectively. Investigation of NU7026 metabolism profiles in plasma and urine indicated that the compound undergoes multiple hydroxylations. A glucuronide conjugate of a bis-hydroxylated metabolite represented the major excretion product in urine. Identification of the major oxidation site as C-2 of the morpholine ring was confirmed by the fact that the plasma clearance of NU7107 (an analogue of NU7026 methylated at C-2 and C-6 of the morpholine ring) was four-fold slower than that of NU7026. The pharmacokinetic simulations performed predict that NU7026 will have to be administered four times per day at 100 mg kg À1 i.p. in order to obtain the drug exposure required for radiosensitisation.

show abstract

Section: Discussionsupporting

confidence: 81%

Preclinical pharmacokinetics and metabolism of a novel prototype DNA-PK inhibitor NU7026

et al. 2005

View full text Add to dashboard Cite

show abstract

“…Several tertiary N ‐oxides have been shown to readily degrade to other products. In acidic medium, N‐ oxide undergoes protonation, and further protonated product undergoes the elimination of neutral formaldehyde to generate Product I , that is, formation of N ‐ demethylated product 32 …”

Section: Resultsmentioning

confidence: 99%

Method validation and characterization of stress degradation products of azelastine hydrochloride using LC‐UV/PDA and LC‐Q/TOF‐MS studies

Shekhar,

Bali

2024

Rapid Comm Mass Spectrometry

View full text Add to dashboard Cite

RationaleAzelastine HCl is a second‐generation H1‐receptor antagonist approved by the US Food and Drug Administration (US FDA) for treating seasonal allergic rhinitis and non‐allergic vasomotor rhinitis. This study encompasses the validation of a liquid chromatography‐ultra violet photo diode array (LC‐UV/PDA) method for the drug and its extension to liquid chromatography/quadrupole time‐of‐flight mass spectrometry (LC‐Q/TOF‐MS) studies for identification and characterization of various stress degradation products of the drug.MethodsStress degradation of azelastine HCl was undertaken under the International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) prescribed conditions of hydrolytic, photolytic, oxidative, and thermal stress. The degraded drug solutions were analyzed using Ultra Performance Liquid Chromatography (UPLC) employing a C18 (100 × 4.6 mm; 2.6 μ, Kinetex) column by isocratic elution. Detection wavelength was 241 nm. The degradation products were identified and characterized using UPLC‐MS/TOF studies, and an attempt was made to isolate one of the degradation products by solvent extraction.ResultsThe drug was found to significantly degrade under acidic/alkaline/neutral photolytic, oxidative, and alkaline hydrolytic conditions. Six degradation products (I–VI) were identified through LC‐Q/TOF‐MS studies that were adequately resolved from the drug with the developed UPLC method. All degradation products (I–VI) were ionized in the total ion chromatogram (TIC) in the LC‐MS studies, and these were identified and characterized, and the degradation pathway of the drug was postulated. One of the oxidation products isolated from the degraded drug solution was characterized through differential scanning calorimetry, Fourier‐transform infrared spectroscopy, and nuclear magnetic resonance spectral data.ConclusionsSix degradation products generated from stress degradation studies on azelastine HCl were adequately resolved through LC‐UV/PDA studies followed by method validation. These were successfully identified and characterized through LC‐Q/TOF‐MS studies, and the degradation pathways for the generation of these products from the drug have been postulated.

show abstract

“…This reaction mechanism has been reported for oxidative degradation of a morpholine acetal substance P antagonist. 39…”

Section: Discussionmentioning

confidence: 99%

Identification and characterization of stress degradation products of ibrutinib by LC-UV/PDA and LC-Q/TOF-MS studies

Mondal,

Bali,

Sharma

2023

Eur J Mass Spectrom (Chichester)

View full text Add to dashboard Cite

The anticancer drug ibrutinib was subjected to stress degradation studies under the ICH-prescribed hydrolytic, photolytic, oxidative and thermal stress conditions, and its degradation behavior was studied. A significant degradation was noted for the drug under acidic/alkaline hydrolytic, acid/alkaline photolytic, and oxidative conditions. The UPLC-UV/PDA studies revealed the generation of six degradation products (I–VI), and these were adequately resolved from the drug under the developed chromatographic conditions over a Kinetex® C18 (100 mm×4.6 mm; 2.6 μm) column employing isocratic elution method. Detection wavelength was selected as 289 nm. The UPLC-UV/PDA method conditions were extrapolated to UPLC-MS/TOF studies. All the six degradation products were found to be ionized in the total ion chromatogram, and the products could be identified and characterized from their mass spectral data. The possible degradation route of ibrutinib leading to generation of various products was also postulated.

show abstract

Novel rearrangements of an N-oxide degradate formed from oxidation of a morpholine acetal substance P antagonist

Cited by 9 publications

References 13 publications

Preclinical pharmacokinetics and metabolism of a novel prototype DNA-PK inhibitor NU7026

Preclinical pharmacokinetics and metabolism of a novel prototype DNA-PK inhibitor NU7026

Method validation and characterization of stress degradation products of azelastine hydrochloride using LC‐UV/PDA and LC‐Q/TOF‐MS studies

Identification and characterization of stress degradation products of ibrutinib by LC-UV/PDA and LC-Q/TOF-MS studies

Contact Info

Product

Resources

About