| 1. |
- Adrian Meredith, Jenny, 1971-, et al.
(författare)
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Design and Synthesis of BACE-1 Inhibitors Containing a New Hydroxyethylene (HE) Scaffold: Potent activities in a cellular assay
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- In a preceding report from our group we disclosed the development of a novel HE transition state isostere with a difluorophenoxymethyl side chain in the P1 position and a methoxy group in the P1’ position furnishing highly potent inhibitors of BACE-1 (i.e. lead compound 1), which moreover exhibit very promising selectivity over cathepsin D. In a continuation of this work with the aim at improving on the cell-based activity and pharmacokinetic properties, we have further developed the SAR for the P1 side chain of inhibitor 1 whereby the P1 side chain oxygen has been substituted for an amine, a carbon or a bond. The chemistry developed for the previous HE inhibitor structure 1 has now been extended to readily accommodate the introduction of new P1 side chains into this new HE scaffold. These modifications have given rise to several highly potent inhibitors where the most potent displayed a BACE-1 Ki value of 0.2 nM and a cell-based Aβ40 IC50 value of 9 nM. Thus, regarding the enzyme inhibition in the cell assay a more than 600-fold improvement compared to compound 1 was achieved via minor structural alterations.
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| 2. |
- Ekegren, Jenny, 1976-
(författare)
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Design and Synthesis of Novel HIV-1 Protease Inhibitors Comprising a Tertiary Alcohol in the Transition-State Mimic
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- HIV-1 protease inhibitors are important in the most frequently used regimen for the treatment of HIV/AIDS, the highly active antiretroviral therapy (HAART). For patients with access to this treatment, an HIV infection is no longer lethal, but rather a manageable, chronic infection. However, the HIV-1 protease inhibitors are generally associated with serious shortcomings such as adverse events, development of drug resistance and poor pharmacokinetic properties. Most of the approved inhibitors suffer from high protein binding, rapid metabolism and/or low membrane permeability. In this project, novel HIV-1 protease inhibitors comprising a rarely used tertiary alcohol in the transition-state mimic were designed, synthesized and evaluated. The rationale behind the design was to achieve ‘masking’ of the tertiary alcohol by for example, intramolecular hydrogen bonding, which was believed could enhance transcellular transport. A reliable synthetic protocol was developed and a series of highly potent inhibitors was obtained exhibiting excellent membrane permeation properties in a Caco-2 cell assay. However, the cellular antiviral potencies of these compounds were low. In an attempt to improve the anti-HIV activity, microwave-accelerated, palladium-catalyzed cross-coupling reactions and aminocarbonylation of aryl bromide precursors were employed to produce P1'-extended test compounds. Inhibitors demonstrating up to six times higher antiviral effect were obtained, the best derivatives having para 3- or 4-pyridyl elongations in P1'.Fast metabolic degradation was observed in liver microsome homogenate, which is believed, at least partly, to be attributable to benzylic oxidation of the indanol P2 group of the inhibitors. To enable facile variation of the P2 side chain a new synthetic route was developed using an enantiomerically pure, benzyl-substituted epoxy carboxylic acid as the key intermediate. Cyclic and amino-acid-residue-derived P2 groups were evaluated, and inhibitors equipotent to the series containing an indanol moiety were produced.
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| 3. |
- Hallberg, Jenny
(författare)
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Factors associated with lung function impairment in children and adults with obstructive lung disease
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Obstructive lung diseases are a group of diseases in which there is a limitation in the flow of air into or out of the lungs. Two common such diseases are asthma, which is found in both children and adults, and chronic obstructive pulmonary disease (COPD), mainly found in the population over 50 years of age. Both asthma and COPD seem to have with several different subgroups, or phenotypes, which may be associated with different long term consequences in regard to morbidity and in some cases also mortality. To be able to prevent and treat these diseases in the best possible way, we need to learn more about the different phenotypes and the mechanisms behind them. The aim of this thesis was to study factors that are associated with lung function impairment in children and adults with obstructive lung diseases. The factors that are in focus are age of onset, duration of symptoms, sex, allergy, smoking and the contribution of genes and environment. We have, in the two first papers, measured lung function at age 4 and 8 years in a birth cohort of 4,000 children and found that asthma symptom onset in the first 4 years of life was, on a group level, associated with impaired exhaled flows. This was found irrespective of the persistence of symptoms between the age of 4 and 8. We could also show tracking of impaired flows between the age of 4 and 8. Sensitization to airway allergens was associated with lung function impairment only in children with symptom onset after the age of 4. While male sex was a risk factor for asthma symptoms, girls with asthma symptoms showed a larger negative effect on exhaled flows, at least in the four first years. In paper 3 and 4, we studied symptom data from 45,000 twins from the Swedish Twin Registry to quantify heritability for chronic bronchitis and emphysema, two of the main components seen in COPD. As smoking behaviour has genetic influences, it was necessary to study how heritability for disease was associated with heritability for smoking. The results showed that ~40% of the individuals liability to developing chronic bronchitis/emphysema can be attributed to genetic factors, and that only a small part of these factors were found to be in common with those influencing smoking habits. Women more often reported chronic bronchitis/emphysema, compared to men, and this could not be explained by different smoking habits or different genes. Two hundred of the twins took part in a clinical testing of different lung function measures. The results from this study showed that all lung function measures that were studied had a heritable component, and that it was larger for women than for men. In conclusion, we have studied how several different factors are associated with lung function impairment in children and adults with obstructive lung disease. In summary, the first years of life are of importance for future lung function. Children that outgrow their asthma seem, on a group level, to loose their symptoms rather their lung function impairment, which might be present through life. We have furthermore shown that genes are important for the individuals liability to disease in adult life. Sex differences exist both in children and adult disease, and there are indications of a less favourable outcome for girls/women. More work is now needed to find the individuals that belong to these susceptible groups, and to develop and apply methods to prevent and treat impaired lung function and disease.
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| 4. |
- Johansson, Jenny, et al.
(författare)
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Gamma-Hydroxybutyrate (GHB) elevates Met-enkephalin-Arg6Phe7 (MEAP) levels in the frontal cortex of the male rat brain
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Gamma-hydroxybutyrate (GHB) has increased in popularity among adolescents during recent years. Predominantly it is used as a recreational drug, but frequently also as an anabolic agent due to its ability of releasing growth hormone. The fact that GHB has been reported to be highly addictive and can cause cognitive deficiencies has become a major concern. In this study, we investigated the impact of GHB treatment in rats on the levels of the endogenous opioid peptides Met-enkephalin-Arg6Phe7 (MEAP) and Dynorphin B (DYNB) in various regions of the brain and on the levels of insulin-like growth factor 1 (IGF-1) in plasma. Furthermore, spontaneous explorative behavior and locomotor activity after GHB administration was analyzed in an Open field (OF). The results demonstrated that treatment with GHB did not affect the parameters that were assessed in the OF, nor did it affect the plasma levels of IGF-1. Regarding the opioid peptide levels, the GHB treated rats demonstrated increased immunoreactive (ir) MEAP but not DYNB levels in the frontal cortex, while no significant alterations were observed in caudate putamen, hypothalamus, nucleus accumbens, amygdala, hippocampus and periaqueductal grey. Moreover, in control rats the levels of ir MEAP and ir DYNB seemed well-balanced in many regions and the peptide levels correlated in amygdala, hippocampus and hypothalamus. However, in the GHB-treated animals no such correlation was observed. In conclusion, GHB treatment created an imbalance regarding the opioids MEAP/DYNB and increased the levels of MEAP significantly in regions of the brain that are of importance for the development of drug dependence.
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| 5. |
- Johansson, Jenny, 1980-
(författare)
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The Impact of Growth Hormone and Gamma-Hydroxybutyrate (GHB) on Systems Related to Cognition
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Drug dependence is a serious and increasing problem in our society, especially among adolescents. The use of the large variety of substances available can result in a range of physiological and psychological adverse effects on individuals and negative consequences on the society overall. Several different types of drugs induce neurotoxicological damages, which in turn can generate impairment in for example the reward system and affect cognitive parameters. The drug gamma-hydroxybutyrate (GHB) is usually considered a harmless compound among abusers, but has now shown to be highly addictive. Furthermore, GHB can cause memory impairments in both humans and animals. On the contrary, growth hormone (GH) and its main mediator insulin-like growth factor 1 (IGF-1) have recently been suggested to improve memory and learning in several studies. The hormones exhibit certain neuroprotective capabilities and have also previously been demonstrated to reverse opioid induced apoptosis in hippocampal cells. These effects and the fact that GHB is shown to increase GH secretion, which attracted considerable attention among body builders, led us to initiate studies on GHB and its impact on relevant systems in the central nervous system (CNS). Thus, the main purpose of the present investigation was to elucidate some of the underlying mechanisms that could account for the effects exerted by GH and GHB in the CNS.We found that a) GH affects the density and functionality of GABAB-receptors and opioid receptors in the male rat brain, b) GHB induces cognitive deficits and down-regulates GABAB-receptors, c) GHB treatment creates an imbalance between the endogenous opioids Met-enkaphalin-Arg6Phe7 (MEAP) and dynorphin B and increases the levels of MEAP in regions of the brain that are associated with drug dependence, and d) GHB affects the expression of IGF-1 receptors but not the plasma levels of IGF-1. In conclusion, the present work demonstrates that GH interacts with both opioid and GABAB-receptors in the male rat CNS and that GHB has an impact on brain regions associated with cognition and the development of dependence. These observations may be of relevance in many aspects related to addiction and might be translated into humans.
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| 6. |
- Melen, Erik, et al.
(författare)
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Spirometric phenotypes from early childhood to young adulthood - A CADSET (Chronic Airway Disease Early Stratification) study
- 2020
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Ingår i: European Respiratory Journal. - : ERS Publications. - 0903-1936 .- 1399-3003. ; 56:Suppl 64
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Results from longitudinal cohort studies show that the lower the lung function in childhood and adulthood, the higher the risk of later chronic airway disease such as COPD. Yet, reliable data is sparse on the prevalence of different types of lung function impairments in the general population of children and young adults, as well as their major determinants.Aim: To report age- and sex-specific prevalences and characteristics of spirometric phenotypes from childhood up to young adulthood.Methods: Lung function data from independent European population-based cohorts involved in the CADSET collaboration were analysed. Pre-bronchodilator FEV1 and FVC data from each cohort were converted into z-scores according to the Global Lung Initiative (GLI) reference system. Overall fit with the GLI spirometry equations was assessed. Airway limitation was defined as a FEV1/FVC z-score < -1.65.Results: Five cohorts provided spirometry data from 10,842 observations in subjects aged 7 to 25 years. Airway limitation was found in around 6-10% across all ages in the cohorts. No evidence of differences between males and females in different age groups were observed. In unadjusted analyses of all cohorts, we found maternal smoking during pregnancy to be associated with airway limitation (p<0.05).Conclusion: Analyses of spirometry data from population-based cohorts in Europe show that the prevalence of airflow limitation according to GLI is substantial (6-10%) and quite similar across cohorts and age groups. These results suggest that airflow limitation can develop early in life and that there are rather small changes in prevalence during childhood.
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| 7. |
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| 8. |
- Rydberg, Tomas, 1962, et al.
(författare)
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Emissions of additives from plastics in the societal material stock – a case study for Sweden
- 2012
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Ingår i: Handbook of Environmental Chemistry. - Berlin, Heidelberg : Springer Berlin Heidelberg. - 1867-979X. ; 18, s. 253-264, s. 253-264
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Estimating the size of the problems related to release, fate, exposure and effects from the human use of chemical substances in materials and consumer products is daunting. More than 100,000 chemical substances are in commercial use and a reasonable description of their existence in, and release from, plastic polymers, glues, paints, fibres, lubricants etc. comprise a big challenge. Here we report the initial results from a generic emission model that has been developed and applied to estimate emissions of a set of organic chemicals from products. The scope of the study was to estimate emissions from products containing plastic materials during their average lifetime within the geographical boundaries of Sweden. The results show that approximately 2% of the plastic additives are emitted annually. Plasticisers, flame retardants, organic pigments and stabilizers are the use categories of additives that are emitted in the largest quantities. Until now, the method has only been used to estimate emissions of additives from plastic materials, but it is believed to also be applicable to other materials.
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| 9. |
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