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| 3. |
- Gu, Chungang, et al.
(författare)
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Lipid Peroxide-Mediated Oxidative Rearrangement of the Pyrazinone Carboxamide Core of Neutrophil Elastase Inhibitor AZD9819 in Blood Plasma Samples
- 2015
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Ingår i: Drug Metabolism And Disposition. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 0090-9556 .- 1521-009X. ; 43:10, s. 1441-1449
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Tidskriftsartikel (refereegranskat)abstract
- This study focused on the mechanistic interpretation of ex vivo oxidation of a candidate drug in blood plasma samples. An unexpected lipid peroxide-mediated epoxidation followed by a dramatic rearrangement led to production of a five-membered oxazole derivative from the original six-membered pyrazinone-carboxamide core of a human neutrophil elastase inhibitor, 6-(1-(4-cyanophenyl)-1H-pyrazol-5-yl)-N-ethyl-5-methyl-3-oxo-4-(3-(trifluoromethyl) phenyl)-3,4-dihydropyrazine-2-carboxamide (AZD9819). The rearranged oxidation product 2-(1-(4-cyanophenyl)-1H-pyrazol-5-yl)-5-(N-ethylacetamido)-N-(3-(trifluoromethyl)phenyl)oxazole-4-carboxamide was characterized by accurate-mass tandem mass spectrometry fragmentations, by two-dimensional NMR and X-ray crystallography of an authentic standard, and by incorporation of an O-18 atom from molecular O-18(2) to the location predicted by our proposed mechanism. The lipid peroxide-mediated oxidation was demonstrated by using human low-density lipoprotein (LDL) in pH 7.4 phosphate buffer and by inhibiting the oxidation with ascorbic acid or L-glutathione, two antioxidants effective in both plasma and the LDL incubation. A nucleophilic mechanism for the epoxidation of AZD9819 by lipid hydroperoxides explains the prevention of its ex vivo oxidation by acidification of the plasma samples. The discovery of the lipid peroxide-dependent oxidation of an analyte and the means of prevention could provide valuable information for biotransformation and bioanalysis.
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- Hammarström, Lars G. J., et al.
(författare)
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The Oncolytic Efficacy and in Vivo Pharmacokinetics of [2-(4-Chlorophenyl)quinolin-4-yl](piperidine-2-yl)methanol (Vacquinol-1) Are Governed by Distinct Stereochemical Features
- 2016
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 59:18, s. 8577-8592
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Tidskriftsartikel (refereegranskat)abstract
- Glioblastoma remains an incurable brain cancer. Drugs developed in the past 20 years have not improved the prognosis for patients, necessitating the development of new treatments. We have previously reported the therapeutic potential of the quinoline methanol Vacquinol-1 (1) that targets glioblastoma cells and induces cell death by catastrophic vacuolization. Compound 1 is a mixture of four stereoisomers due to the two adjacent stereogenic centers in the molecule, complicating further development in the preclinical setting. This work describes the isolation and characterization of the individual isomers of 1 and shows that these display stereospecific pharmacokinetic and pharmacodynamic features. In addition, we present a stereoselective synthesis of the active isomers, providing a basis for further development of this compound series into a novel experimental therapeutic for glioblastoma.
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- Johnson, Matthew Stanley, et al.
(författare)
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Gas-phase advanced oxidation for effective, efficient in situ control of pollution
- 2014
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Ingår i: Environmental Science and Technology. - : American Chemical Society (ACS). - 0013-936X .- 1520-5851. ; 48:15, s. 8768-8776
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Tidskriftsartikel (refereegranskat)abstract
- In this article, gas-phase advanced oxidation, a new method for pollution control building on the photo-oxidation and particle formation chemistry occurring in the atmosphere, is introduced and characterized. The process uses ozone and UV-C light to produce in situ radicals to oxidize pollution, generating particles that are removed by a filter; ozone is removed using a MnO2 honeycomb catalyst. This combination of in situ processes removes a wide range of pollutants with a comparatively low specific energy input. Two proof-of-concept devices were built to test and optimize the process. The laboratory prototype was built of standard ventilation duct and could treat up to 850 m3/h. A portable continuous-flow prototype built in an aluminum flight case was able to treat 46 m3/h. Removal efficiencies of >95% were observed for propane, cyclohexane, benzene, isoprene, aerosol particle mass, and ozone for concentrations in the range of 0.4-6 ppm and exposure times up to 0.5 min. The laboratory prototype generated a OH * concentration derived from propane reaction of (2.5 ± 0.3) × 1010 cm-3 at a specific energy input of 3 kJ/m3, and the portable device generated (4.6 ± 0.4) × 109 cm-3 at 10 kJ/m3. Based on these results, in situ gas-phase advanced oxidation is a viable control strategy for most volatile organic compounds, specifically those with a OH* reaction rate higher than ca. 5 × 10-13 cm3/s. Gas-phase advanced oxidation is able to remove compounds that react with OH and to control ozone and total particulate mass. Secondary pollution including formaldehyde and ultrafine particles might be generated, depending on the composition of the primary pollution.
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- Malm, Annika, et al.
(författare)
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Sustainable economic level of leakage in Norway and Sweden – manual of practice
- 2020
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Ingår i: Water practice and technology. - : IWA Publishing. - 1751-231X. ; 15:2, s. 343-349
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Tidskriftsartikel (refereegranskat)abstract
- Awareness of water’s value, high water losses, occasional water shortages and increased costs arising from new treatment requirements has increased focus on reducing water losses. For water loss management, SELL (sustainable economic level of leakage), can be used. SELL includes not only the long-term utility costs and benefits, but also external social and environmental leakage costs, including traffic disruption during pipe repair and replacement work, carbon footprints and health risk effects from leaking pipes with inadequate pressure. The aim of the project was to adapt SELL to Norwegian and Swedish conditions and prepare a calculation model for SELL for use by water utilities. A spreadsheet was developed to calculate water balances and leakage. Another was developed for calculating SELL for the utility. The latter spreadsheet includes researchbased default values if no local data are available. An uncertainty analysis was used to show how much input data uncertainty affects the result. The conclusions are that, when all externalities are included and new leak reduction techniques are developed, SELL is lower than expected. The authors believe that the manual will help significantly in fighting water losses, especially for small-and medium-scale water utilities.
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- Scott, James S., et al.
(författare)
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Circumventing seizure activity in a series of G protein coupled receptor 119 (GPR119) agonists
- 2014
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society. - 0022-2623 .- 1520-4804. ; 57:21, s. 8984-8998
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Tidskriftsartikel (refereegranskat)abstract
- Agonism of GPR119 is viewed as a potential therapeutic approach for the treatment of type II diabetes and other elements of metabolic syndrome. During progression of a previously disclosed candidate 1 through mice toxicity studies, we observed tonic-clonic convulsions in several mice at high doses. An in vitro hippocampal brain slice assay was used to assess the seizure liability of subsequent compounds, leading to the identification of an aryl sulfone as a replacement for the 3-cyano pyridyl group. Subsequent optimization to improve the overall profile, specifically with regard to hERG activity, led to alkyl sulfone 16. This compound did not cause tonic-clonic convulsions in mice, had a good pharmacokinetic profile, and displayed in vivo efficacy in murine models. Importantly, it was shown to be effective in wild-type (WT) but not GPR119 knockout (KO) animals, consistent with the pharmacology observed being due to agonism of GPR119.
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- Svensson, M., et al.
(författare)
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Process Simulation and Automatic Path Planning of Adhesive Joining
- 2016
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Ingår i: Procedia CIRP. - : Elsevier B.V.. - 2212-8271. ; , s. 298-303
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Konferensbidrag (refereegranskat)abstract
- Adhesive joining is frequently used in the automotive industry. In the pursuit of reducing weight, adhesive joining is important due to the possibility of joining different types of materials. The process is often automatised in order to reduce cycle time. In this paper we aim to present a novel framework that includes detailed process simulation and automatic generation of collision free robot paths and in this way improve the quality of the joint and reduce both cycle time and processing time. To verify the simulations, the properties of the adhesive bead have been compared to experiments with good agreement. © 2016 The Authors.
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