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- Gising, Johan, 1981-, et al.
(författare)
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Achiral Pyrazinone-Based Inhibitors of the Hepatitis C Virus NS3 Protease and Drug-Resistant Variants with Elongated Substituents Directed Toward the S2 Pocket
- 2014
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 57:5, s. 1790-1801
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Tidskriftsartikel (refereegranskat)abstract
- Herein we describe the design, synthesis, inhibitory potency, and pharmacokinetic properties of a novel class of achiral peptidomimetic HCV NS3 protease inhibitors. The compounds are based on a dipeptidomimetic pyrazinone glycine P3P2 building block in combination with an aromatic acyl sulfonamide in the P1P1′ position. Structure–activity relationship data and molecular modeling support occupancy of the S2 pocket from elongated R6 substituents on the 2(1H)-pyrazinone core and several inhibitors with improved inhibitory potency down to Ki = 0.11 μM were identified. A major goal with the design was to produce inhibitors structurally dissimilar to the di- and tripeptide-based HCV protease inhibitors in advanced stages of development for which cross-resistance might be an issue. Therefore, the retained and improved inhibitory potency against the drug-resistant variants A156T, D168V, and R155K further strengthen the potential of this class of inhibitors. A number of the inhibitors were tested in in vitro preclinical profiling assays to evaluate their apparent pharmacokinetic properties. The various R6 substituents were found to have a major influence on solubility, metabolic stability, and cell permeability.
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| 2. |
- Johansson, Sheshti, et al.
(författare)
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How the choice of biofuel system in a small-scale Swedish organic farm affects food production and NPK balance
- 2014
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Ingår i: Acta Agriculturae Scandinavica, Section B - Soil and Plant Science. - : Informa UK Limited. - 0906-4710 .- 1651-1913. ; 64, s. 109-120
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Tidskriftsartikel (refereegranskat)abstract
- Modern agriculture is causing extensive environmental damage. Arguments have been put forward that a systemic change is needed in agriculture to address the major environmental challenges faced by mankind. This is a case study of a research farm whose aim is to form a farming system that has a minimal impact on carbon and nitrogen cycles while maintaining biodiversity. For the farm to minimise its impact on the global carbon cycle and associated climate change, it is important to reduce fossil energy use. The research farm has minimised all its inputs, but uses a diesel-run tractor. Agriculture's primary function is to provide food of adequate quality. The hypothesis of this study is that using biomass from arable land for tractor work on the farm would reduce the amount of food produced relative to using fossil fuel for tractor work. The objective of this paper was to develop scenarios for biomass-derived tractor work for the study farm chosen and to investigate their impact on food production. Food availability was measured by the number of people the farm could supply, denoted as Np. A farm nitrogen, phosphorus and potassium (NPK) balance was also applied to the different scenarios. The investigated scenarios for replacing fossil fuel tractor work were draught horsepower combined with cold-pressed rape-seed oil in a tractor, ethanol from wheat produced in a conventional ethanol plant, and farm-made ethanol from potatoes. Using wheat and potato to produce ethanol reduced food production by 23% and 18% respectively, compared to using conventional diesel. Combining a draught horse and on-farm cold-pressed rapeseed oil only reduced the food production by 6%. N is maintained in all scenarios due to the nitrogen-fixing leys. P can be maintained in the fields if bones are recycled, but nutrients, especially K, are moved from meadow to field.
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