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  • 1.
    Agalo, Faith
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Synthesis of Insulin-Regulated Aminopeptidase (IRAP) inhibitors2015Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    The need for alternative cognitive enhancers has risen due to the fact that clinical trial results of the drugs currently approved for treating these disorders have not been satisfactory.

    IRAP has become a possible drug target for treating cognitive impairment brought about by Alzheimer’s disease, head trauma or cerebral ischemia, among others. This came after the revelation that Angiotensin IV enhances memory and learning. Angiotensin IV, the endogenous ligand of IRAP has been structurally modified with the aim of producing potent IRAP inhibitors. However, the peptidic nature of these inhibitors restricts their use; they are not likely to cross the blood brain barrier.

    Other strategies for generating IRAP inhibitors have been through structure-based design and receptor based virtual screening. These drug-like molecules have exhibited positive results in animal studies.

    IRAP inhibitors have been identified via a HTS of 10500 low-molecular weight compounds to give the hit based on a spirooxindole dihydroquinazolinone scaffold, with an IC50 value of 1.5 µM. In this project, some analogues to this hit compound have successfully been synthesized using a known method, whereas others have been synthesized after additional method development.

    The application of the developed method was found to be limited, because poor yield was obtained when a compound with an electron withdrawing substituent on the aniline was synthesized. As a result of this, modification of this method may be required or new methods may have to be developed to synthesize these types of analogues.

    Inhibition capability of 5 new spirooxindole dihydroquinazolinones was tested through a biochemical assay. Compound 6e emerged as the most potent inhibitor in the series, with an IC50 value of 0.2 µM. This compound will now serve as a lead compound and should be used as a starting point for future optimization in order to generate more potent IRAP inhibitors.

     

  • 2.
    Hallberg, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Schaal, Wesley
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Olofsson, Kristofer
    Pelcman, Benjamin
    Sanin, Andrei
    Pyrazole compounds useful in the treatment of inflammation 2004Patent (Other (popular science, discussion, etc.))
  • 3.
    Jama, Fosia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Evaluation of amino acids in Aminoven 10 % and Vamin 18EF with UPLC using Waters AccQTag method2013Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    The aim with this project was to evaluate Waters AccQTag method which was ananalytical method that Waters Corporation provides for determination of aminoacids. The amino acid analysis was carried out by reversed-phase AQUITY UPLCH-Class, using a BEH C18-column and a PDA detector.Both primary and secondary amino acids were analyzed after precolumnderivatization with the AccQTag reagent kit by a manual procedure and, detected at260 nm. Fresenius Kabis existing products, Aminoven 10 % and Vamin 18EF wereused as samples. The evaluation was based on external calibration curves withprepared standard solutions from Fresenius Kabi, with the addition of the internalstandard L-Norvaline. Waters amino acid standard was used for the system suitabilitytest. A validation according to the ICH guidelines were performed with the followingparameters: specificity, linearity, precision, LOQ, LOD and robustness.Complementary parameters for system suitability test (SST) and stability of standardand reagent were also evaluated. The validation showed that the % RSD values forspecificity, system suitability test and robustness were within the acceptance criteriaof equal or less than 3 % for amino acids. Although the precision were between1.3-7.5 % which was higher than the acceptance criteria of equal or less than 3 %, thiswas likely due to sensitive sample preparation. The linearity was bad which made itimpossible to quantify the method since the calibration curves were below 0.999. Itwas concluded that the system was robust and can be used to analyze amino acids inAminoven 10 % and Vamin 18EF but the preparation step should if possible beautomatized to achieve better precision in the analytical work. Two amino acids,cysteine and histidine, needs to be studied further; cysteine gave three peaks insteadof one and histidine gave a peak split at higher injection volume than 0.5 uL.

  • 4.
    Lindh, Martin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Svensson, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Schaal, Wesley
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Zhang, Jin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sköld, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Brandt, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Karlén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Toward a Benchmarking Data Set Able to Evaluate Ligand- and Structure-based Virtual Screening Using Public HTS Data2015In: Journal of Chemical Information and Modeling, ISSN 1549-9596, Vol. 55, no 2, p. 343-353Article in journal (Refereed)
    Abstract [en]

    Virtual screening has the potential to accelerate and reduce costs of probe development and drug discovery. To develop and benchmark virtual screening methods, validation data sets are commonly used. Over the years, such data sets have been constructed to overcome the problems of analogue bias and artificial enrichment. With the rapid growth of public domain databases containing high-throughput screening data, such as the PubChem BioAssay database, there is an increased possibility to use such data for validation. In this study, we identify PubChem data sets suitable for validation of both structure- and ligand-based virtual screening methods. To achieve this, high-throughput screening data for which a crystal structure of the bioassay target was available in the PDB were identified. Thereafter, the data sets were inspected to identify structures and data suitable for use in validation studies. In this work, we present seven data sets (MMP13, DUSP3, PTPN22, EPHX2, CTDSP1, MAPK10, and CDK5) compiled using this method. In the seven data sets, the number of active compounds varies between 19 and 369 and the number of inactive compounds between 59 405 and 337 634. This gives a higher ratio of the number of inactive to active compounds than what is found in most benchmark data sets. We have also evaluated the screening performance using docking and 3D shape similarity with default settings. To characterize the data sets, we used physicochemical similarity and 2D fingerprint searches. We envision that these data sets can be a useful complement to current data sets used for method evaluation.

  • 5.
    Liti, Samone
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Evaluation of sample preparation techniques for MALDI-TOF-MS analysis of oligosaccharides2016Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    The aim of this study was to optimize the sample preparation and methods for analysis of oligosaccharides of hyaluronic acid with MALDI- TOF-MS. The analysis was carried out on an Autoflex speed MADLI-TOF- MS instrument with both linear and reflectron mode. Matrices used in this study were 2,5-DHB and Super-DHB and type of matrix was chosen depending on the size of the analyzed oligosaccharides. The application of sample and matrix on the target that gave the most homogenous crystallization was sandwich and the laser power in the MALDI was kept at 65 %. Since it is known that salts and buffers interfere with the analysis, sample clean-up such as solid phase extraction (SPE) in pipette tips and dialysis was performed. SPE worked best for low mass oligosaccharides and provided high intensity and little noise. With SPE a concentration of the analyte could be done which was the advantage over dialysis. Dialysis worked well for larger oligosaccharides and mixtures of different sized oligosaccharides. Another way of using MALDI for biomolecule analysis is with TLC-MALDI. A fast and accurate separation was achieved and analysis could be done directly from the plate. The optimized methods were evaluated according to linearity and precision, LOD, mass accuracy and matrix stability. The linearity and precision was good in a higher concentration range (50 μg/mL and higher), but the test for limit-of-detection (LOD) indicated that concentrations from 20-30 μg/mL could be analyzed with no interference from the background. The mass accuracy was within the acceptable limits according to Bruker Daltonics when a mass calibration was done for each analyzed sample. The stability of the matrix in solution was difficult to study because of the day-to-day variation in intensities given by the MALDI-TOF-MS technique. 

  • 6.
    Nordeman, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Development of Palladium-Promoted 11C/12C-Carbonylations and Radiosynthesis of Amyloid PET Ligands2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In the first part of this thesis, palladium(0)-catalyzed and -mediated carbonylations are discussed. Paper I describes a new method for the safe, efficient use of a solid carbon monoxide source in the synthesis of primary and secondary benzamides. In total, 35 benzamides were synthesized from aryl iodides (20 examples, 69-97% yield) and aryl bromides (15 examples, 32-93% yield). Reduction-prone groups were used successfully in the reactions. In paper II, the same protocol was adopted for the palladium(0)-catalyzed synthesis of N-cyanobenzamides from aryl iodides/bromides, carbon monoxide and cyanamide. In total, 22 N-cyanobenzamides were synthesized (42-88% yield). The radiosynthesis of [11C]N-cyanobenzamides is discussed in paper III. In total, 22 compounds were synthesized from various aryl halides in 28-79% decay corrected radiochemical yield. The protocol was then applied to the radiosynthesis of [11C]N-cyanobenzamide analogs of flufenamic acid and dazoxibene.

    In the second part of this thesis, compounds of interest in relation to amyloid diseases are discussed. Paper IV describes the solid-phase synthesis of BACE-1 enzyme inhibitors containing secondary and tertiary hydroxyl as the transition state isostere. In total, 22 inhibitors were synthesized. The most potent compound (IC50= 0.19 µM) was co-crystallized at the active site of the enzyme to reveal a new binding mode. In paper V, the evaluation of a potent BACE-1 inhibitor as a potential radiotracer for use in PET is described. The radiolabeled [11C]BSI-IV was obtained in 29±12% decay corrected radiochemical yield by a three-component palladium(0)-mediated aminocarbonylation. Its properties as a potential PET tracer were investigated in vitro by autoradiography and in vivo in rats using small animal PET-CT. A new class of amyloid-binding PET ligands is described in paper VI. Three polythiophenes were labeled with carbon-11 or fluorine-18 (26-43% decay-corrected radiochemical yield). The in vitro studies showed that these ligands bind specifically to amyloid deposits. In vivo PET showed low uptake in the organs of interest in healthy rats and a monkey. These results suggest the labeled thiophenes derivatives could be useful as PET tracers for the study of amyloid diseases.

    List of papers
    1. Aminocarbonylations Employing Mo(CO)(6) and a Bridged Two-Vial System: Allowing the Use of Nitro Group Substituted Aryl Iodides and Aryl Bromides
    Open this publication in new window or tab >>Aminocarbonylations Employing Mo(CO)(6) and a Bridged Two-Vial System: Allowing the Use of Nitro Group Substituted Aryl Iodides and Aryl Bromides
    2012 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 77, no 24, p. 11393-11398Article in journal (Refereed) Published
    Abstract [en]

    A bridged two-vial system aminocarbonylation protocol where Mo(CO)(6) functions as an external in situ solid source of CO has been developed. For the first time both nitro group containing aryl/heteroaryl iodides and bromides gave good to excellent yields in the Mo(CO)(6)-mediated and palladium(0)-catalyzed conversion to benzamides, while the identical one-vessel protocol afforded extensive reduction of the nitro functionality. The above-mentioned bridged two-compartment protocol furnished good results with both primary amines and secondary amines and sluggish aniline nucleophiles at 65-85 °C reaction temperatures.

    National Category
    Medicinal Chemistry Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-189519 (URN)10.1021/jo302322w (DOI)000312564900046 ()23205569 (PubMedID)
    Funder
    Knut and Alice Wallenberg FoundationSwedish Research Council
    Available from: 2013-01-02 Created: 2013-01-02 Last updated: 2018-01-11Bibliographically approved
    2. Palladium-Catalyzed Carbonylative Synthesis of N-Cyanobenzamides from Aryl Iodides/Bromides and Cyanamide
    Open this publication in new window or tab >>Palladium-Catalyzed Carbonylative Synthesis of N-Cyanobenzamides from Aryl Iodides/Bromides and Cyanamide
    2013 (English)In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 54, no 50, p. 6912-6915Article in journal (Refereed) Published
    Abstract [en]

    A novel and convenient protocol for the synthesis of N-cyanobenzamides starting from readily available aryl halides and cyanamide via palladium-catalyzed aminocarbonylation has been developed. The protocol utilizes Mo(CO)6 as the CO source or CO(gas) and affords the desired N-cyanobenzamides in moderate to good yields.

    National Category
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-212521 (URN)10.1016/j.tetlet.2013.10.040 (DOI)000327285300028 ()
    Available from: 2013-12-11 Created: 2013-12-11 Last updated: 2017-12-06Bibliographically approved
    3. Pd-mediated Carbonylative Synthesis of 11C-N-Cyanobenzamides
    Open this publication in new window or tab >>Pd-mediated Carbonylative Synthesis of 11C-N-Cyanobenzamides
    (English)Manuscript (preprint) (Other academic)
    National Category
    Organic Chemistry
    Research subject
    Chemistry with specialization in Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-213862 (URN)
    Available from: 2014-01-05 Created: 2014-01-05 Last updated: 2014-02-06
    4. Investigation of alpha-phenylnorstatine and alpha-benzylnorstatine as transition state isostere motifs in the search for new BACE-1 inhibitors
    Open this publication in new window or tab >>Investigation of alpha-phenylnorstatine and alpha-benzylnorstatine as transition state isostere motifs in the search for new BACE-1 inhibitors
    Show others...
    2011 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 19, no 1, p. 145-155Article in journal (Refereed) Published
    Abstract [en]

    Inhibition of the BACE-1 protease enzyme has over the recent decade developed into a promising drug strategy for Alzheimer therapy. In this report, more than 20 new BACE-1 protease inhibitors based on α-phenylnorstatine, α-benzylnorstatine, iso-serine, and β-alanine moieties have been prepared. The inhibitors were synthesized by applying Fmoc solid phase methodology and evaluated for their inhibitory properties. The most potent inhibitor, tert-alcohol containing (R)-12 (IC50 = 0.19 μM) was co-crystallized in the active site of the BACE-1 protease, furnishing a novel binding mode in which the N-terminal amine makes a hydrogen bond to one of the catalytic aspartic acids.

    Keywords
    α-Benzylnorstatine, α-Phenylnorstatine, Alzheimer's disease, BACE-1 inhibitors, tert-Hydroxyl, Transition state mimic
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-109026 (URN)10.1016/j.bmc.2010.11.042 (DOI)000285724800014 ()21183353 (PubMedID)
    Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2018-01-13Bibliographically approved
    5. 11C-Labeling of a Potent Hydroxyethylamine BACE-1 Inhibitor and Evaluation in vitro and in vivo
    Open this publication in new window or tab >>11C-Labeling of a Potent Hydroxyethylamine BACE-1 Inhibitor and Evaluation in vitro and in vivo
    Show others...
    2014 (English)In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 41, no 6, p. 536-543Article in journal (Refereed) Published
    Abstract [en]

    Introduction: The enzyme beta-secretase 1 (BACE-1) is associated with the catalytic cleavage of amyloid precursor protein (APP) which leads to the production of amyloid-p, an amyloidogenic peptide that forms insoluble fibrils and is linked to neurodegeneration and Alzheimer's disease (AD). A PET-radioligand for the quantification of BACE-1 would be useful for the understanding of AD. In this report, we describe the synthesis and carbon-11 radiolabeling of a potent hydroxyethylamine BACE-1 enzyme inhibitor (BSI-IV) and its evaluation in vitro and in vivo. Methods: (11)[C]-N-1-((2S,3R)-4-(cyclopropylamino)-3-hydroxy-1-phenylbutan-2-y1)-5-(N-methylmethylsulfonamido)-N-3-((R)-1-phenylethyl)isophthalamide, a p-secretase inhibitor, denoted here as [C-11]BSIIV was synthesized through a palladium-mediated aminocarbonylation with an aryl halide precursor (I or Br) and [C-11]CO. The effect of different palladium/ligand-complexes on radiochemical yield in the carbonylative reaction was investigated. The binding of the labeled compound to BACE-1 enzyme was studied in vitro by frozen section autoradiography from brains of healthy rats. Dynamic small animal PET-CT studies and ex vivo biodistribution were performed in male rats. Results: The halide precursors were synthesized in six steps starting from methyl-3-nitrobenzoate with an overall yield of 21-26%. [C-11]BSI-IV was obtained in 29 +/- 12% decay corrected radiochemical yield (n = 12) with a specific activity of 790 +/- 155 GBq/umol at the end of synthesis with a radiochemical purity of >99%. The predinical studies showed that [C-11]BSI-IV has a rapid metabolism in rat with excretion to the small intestines. Conclusion: [C-11]BSI-IV was obtained in sufficient amount and purity to enable predinical investigation. The predinical studies showed low specific binding in vitro and fast clearance in vivo and a low uptake in the brain. These findings suggests that [C-11]BSI-IV has limited use as a PET-ligand for the study of BACE-1 or AD.

    National Category
    Organic Chemistry Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-213860 (URN)10.1016/j.nucmedbio.2014.03.024 (DOI)000336946400014 ()
    Available from: 2014-01-05 Created: 2014-01-05 Last updated: 2018-01-11Bibliographically approved
    6. 11C and 18F Radiolabeling of Tetra and Pentathiophenes as PET-Ligands for Misfolded Protein Aggregates
    Open this publication in new window or tab >>11C and 18F Radiolabeling of Tetra and Pentathiophenes as PET-Ligands for Misfolded Protein Aggregates
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Cardiac and Cardiovascular Systems Surgery Medicinal Chemistry Organic Chemistry
    Research subject
    Medicinal Chemistry; Chemistry with specialization in Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-213861 (URN)
    Available from: 2014-01-05 Created: 2014-01-05 Last updated: 2018-01-11
  • 7. Olofsson, Kristofer
    et al.
    Pelcman, Benjamin
    Nilsson, Peter
    Schaal, Wesley
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Use of new lipoxygenase inhibitors2005Patent (Other (popular science, discussion, etc.))
  • 8. Olofsson, Kristofer
    et al.
    Suna, Edgars
    Pelcman, Benjamin
    Ozola, Vita
    Katkevics, Martins
    Kalvins, Ivars
    Schaal, Wesley
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Indoles useful in the treatment of inflammation2005Patent (Other (popular science, discussion, etc.))
  • 9. Olofsson, Kristofer
    et al.
    Suna, Edgars
    Pelcman, Benjamin
    Ozola, Vita
    Katkevics, Martins
    Kalvins, Ivars
    Schaal, Wesley
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Indoles useful in the treatment of inflammation2004Patent (Other (popular science, discussion, etc.))
  • 10. Olofsson, Kristofer
    et al.
    Suna, Edgars
    Pelcman, Benjamin
    Ozola, Vita
    Katkevics, Martins
    Kalvins, Ivars
    Schaal, Wesley
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Indoles useful in the treatment of inflammation 2005Patent (Other (popular science, discussion, etc.))
  • 11. Pelcman, Benjamin
    et al.
    Almeida, Maria
    Katkevics, Martins
    Nilsson, Peter
    Schaal, Wesley
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Olofsson, Kristofer
    Bis aromatic compounds for use in the treatment of inflammation 2009Patent (Other (popular science, discussion, etc.))
  • 12. Pelcman, Benjamin
    et al.
    Olofsson, Kristofer
    Kalvins, Ivars
    Suna, Edgars
    Ozola, Vita
    Schaal, Wesley
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Benzoxazoles useful in the treatment of inflammation2007Patent (Other (popular science, discussion, etc.))
  • 13. Pelcman, Benjamin
    et al.
    Olofsson, Kristofer
    Katkevics, Martins
    Ozola, Vita
    Suna, Edgars
    Kalvins, Ivars
    Schaal, Wesley
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Indoles useful in the treatment of inflammation2005Patent (Other (popular science, discussion, etc.))
  • 14. Pelcman, Benjamin
    et al.
    Olofsson, Kristofer
    Katkevics, Martins
    Ozola, Vita
    Suna, Edgars
    Kalvins, Ivars
    Trapencieris, Peteris
    Katkevica, Dace
    Schaal, Wesley
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Indoles useful in the treatment of inflamation 2005Patent (Other (popular science, discussion, etc.))
  • 15. Pelcman, Benjamin
    et al.
    Olofsson, Kristofer
    Katkevics, Martins
    Ozola, Vita
    Suna, Edgars
    Kalvins, Ivars
    Trapencieris, Peteris
    Katkevica, Dace
    Schaal, Wesley
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Indoles useful in the treatment of inflammation 2005Patent (Other (popular science, discussion, etc.))
  • 16. Pelcman, Benjamin
    et al.
    Olofsson, Kristofer
    Schaal, Wesley
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kalvins, Ivars
    Katkevics, Martins
    Ozola, Vita
    Suna, Edgars
    Benzoxazoles useful in the treatment of inflammation2006Patent (Other (popular science, discussion, etc.))
  • 17.
    Ragno, Rino
    et al.
    Sapienza University of Rome.
    Marshall, Garland R.
    Washington University School of Medicine in St. Louis.
    Ballante, Flavio
    Washington University School of Medicine in St. Louis .
    Structure-based modeling and target-selectivity prediction2014Patent (Other (popular science, discussion, etc.))
    Abstract [en]

    The present invention provides, inter alia, methods, models, and systems for selecting an effector having specificity for a target molecule. The methods and systems of the present invention involve several steps, including compiling a database containing structural data for a library of molecules and a population of ligands and activity data, establishing structure-based equivalence of sequence elements in the library of molecules, determining likely spatial orientations of population ligands in library molecules, calculating interaction energies for each ligand-molecule pair, generating statistical models that are predictive of sequence elements likely to contribute to a differential effect of ligands on molecules, selecting an effector that is likely to have a desired specificity for the target molecule, experimentally determining activity data for effector-library molecule pairs, and at least once repeating the steps listed above wherein the effector is a member of the population of ligands.

  • 18. Rönn, Robert
    et al.
    Lindh, Carl
    Ringberg, Erik
    Andersson, Hanna
    Nilsson, Peter
    Schaal, Wesley
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    af Rosenschöld, Magnus Munck
    Nikitidis, Antonios
    Nikitidis, Grigorios
    Johannesson, Petra
    Tyrchan, Christian
    Cyclopropane carboxylic acid derivatives and pharmaceutical uses thereof 2016Patent (Other (popular science, discussion, etc.))
  • 19.
    Öhrngren, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Tertiary Alcohol- or β-Hydroxy γ-Lactam-Based HIV-1 Protease Inhibitors: Microwave Applications in Batch and Continuous Flow Organic Synthesis2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Since the outbreak of the HIV/AIDS pandemic in the 1980s, the disease has cost the lives of over 30 million people, and a further 33 million are currently living with the HIV infection. With the appropriate treatment, HIV/AIDS can today be regarded as a chronic but manageable disease. However, treatment is not available globally and UNAIDS still estimates that there are currently 5000 AIDS-related deaths worldwide per day.

    HIV protease inhibitors (PIs) constitute one of the fundaments of HIV treatment, and are commonly used in so-called highly active antiretroviral therapy (HAART), together with reverse transcriptase inhibitors. Although there are ten PIs on the market, there is still a need for novel structures. The rapid development of resistant strains, due to the high frequency of mutations, together with the commonly observed adverse effects of the drugs available, illustrate the need to develop new potent structures.

    Two novel scaffolds were investigated in this work. A tertiary alcohol-containing scaffold comprising a three-carbon tether, and a β-hydroxy γ-lactam-based scaffold were designed, synthesized and evaluated using enzyme- and cell-based assays. X-ray analyses of inhibitors from each class provided information on inhibitor–protease interactions. The inhibitors containing the tertiary alcohol provided at best an enzymatic inhibition (Ki) of 2.3 nM, and an inhibition in the cell-based assay (EC50) of 0.17 µM. The γ-lactam-based inhibitors exhibited better inhibition than the first series; the best values being Ki = 0.7 nM and EC50 = 0.04 µM.

    The second part of these studies involved the evaluation of a novel non-resonance continuous-flow microwave instrument. The instrument was validated regarding heating capacity, temperature stability and temperature homogeneity. A number of model reactions were performed with low- and high-microwave-absorbing solvents. It was found that the microwave heating source allowed rapid temperature adjustment, together with easily regulated, flow-dependent reaction times, providing an efficient tool for reaction optimisation.

    List of papers
    1. Two-carbon-elongated HIV-1 protease inhibitors with a tertiary-alcohol-containing transition-state mimic
    Open this publication in new window or tab >>Two-carbon-elongated HIV-1 protease inhibitors with a tertiary-alcohol-containing transition-state mimic
    Show others...
    2008 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 51, no 4, p. 1053-1057Article in journal (Refereed) Published
    Abstract [en]

    A new generation of HIV-1 protease inhibitors encompassing a tertiary-alcohol-based transition-state mimic has been developed. By elongation of the core structure of recently reported inhibitors with two carbon atoms and by varying the P1' group of the compounds, efficient inhibitors were obtained with Ki down to 2.3 nM and EC50 down to 0.17 microM. Two inhibitor-enzyme X-ray structures are reported.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-102908 (URN)10.1021/jm070680h (DOI)000253353800037 ()18215014 (PubMedID)
    Available from: 2009-05-12 Created: 2009-05-12 Last updated: 2017-12-13Bibliographically approved
    2. Hiv-1 Protease Inhibitors with a Tertiary Alcohol Containing a Transition-State Mimic and Various P2/P1´ Substituents
    Open this publication in new window or tab >>Hiv-1 Protease Inhibitors with a Tertiary Alcohol Containing a Transition-State Mimic and Various P2/P1´ Substituents
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    2011 (English)In: MedChemComm, ISSN 2040-2503, E-ISSN 2040-2511, Vol. 2, no 8, p. 701-709Article in journal (Refereed) Published
    Abstract [en]

    Two series, including in total 18 novel HIV-1 protease inhibitors, comprising a tertiary alcohol as thetransition-state mimic have been synthesised and evaluated. Replacement of the previously used, butmetabolically unstable, indanol amide group with amino acid derived aliphatic P2–P3 moietiesprovided potent inhibitors with low Ki- and EC50-values (2.7 nM and 2.0 mM, respectively). The P10subunit was varied using 10 different aromatic and heteroaromatic substituents furnishing thecorresponding inhibitors with retained activity. Permeability and stability studies showed examples inthe same range as Atazanavir. X-Ray crystallographic analysis of two selected inhibitor enzyme cocomplexes(9a and 9d) supplied detailed structural information. The binding modes were compared tothose of Atazanavir and a previously reported indanol amide containing inhibitor (14). The novelinhibitors with an elongated P1' side chain enabled a previously unexploited edge-on interaction withPhe53/153. Exchange of the previously used indanol amide P2 moiety, with a tert-leucine derived P2–P3side chain, furnished small main chain displacements in the S2–S3 pocket. The methyl amide in the P3 position caused a 2 Å shift of the Arg8/108 in comparison to 14, indicating the flexibility of the proteaseactive site.

    Keywords
    HIV, protease, inhibitor
    National Category
    Medicinal Chemistry
    Research subject
    Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-135157 (URN)10.1039/c1md00077b (DOI)000295068100003 ()
    Available from: 2010-12-06 Created: 2010-12-06 Last updated: 2018-01-12Bibliographically approved
    3. Synthesis, X-ray Analysis, and Biological Evaluation of a New Class of Stereopure Lactam-Based HIV-1 Protease Inhibitors
    Open this publication in new window or tab >>Synthesis, X-ray Analysis, and Biological Evaluation of a New Class of Stereopure Lactam-Based HIV-1 Protease Inhibitors
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    2012 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 55, no 6, p. 2724-2736Article in journal (Refereed) Published
    Abstract [en]

    In an effort to identify a new class of druglike HIV-1 protease inhibitors, four different stereopure beta-hydroxy gamma-lactam-containing inhibitors have been synthesized, biologically evaluated, and cocrystallized. The impact of the tether length of the central spacer (two or three carbons) was also investigated. A compound with a shorter tether and (3R,4S) absolute configuration exhibited high activity with a K-i of 2.1 nM and an EC50 of 0.64 mu M. Further optimization by decoration of the P1' side chain furnished an even more potent HIV-1 protease inhibitor (K-i = 0.8 nM, EC50 = 0.04 mu M). According to X-ray analysis, the new class of inhibitors did not fully succeed in forming two symmetric hydrogen bonds to the catalytic aspartates. The crystal structures of the complexes further explain the difference in potency between the shorter inhibitors (two-carbon spacer) and the longer inhibitors (three-carbon spacer).

    Keywords
    HIV, AIDS, protease inhibitor, aspartic protease, lactam, tertiary alcohol, X-ray
    National Category
    Medicinal Chemistry
    Research subject
    Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-160186 (URN)10.1021/jm201620t (DOI)000301767000017 ()
    Available from: 2011-10-17 Created: 2011-10-17 Last updated: 2018-01-12Bibliographically approved
    4. Evaluation of a Nonresonant Microwave Applicator for Continuous-Flow Chemistry Applications
    Open this publication in new window or tab >>Evaluation of a Nonresonant Microwave Applicator for Continuous-Flow Chemistry Applications
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    2012 (English)In: Organic Process Research & Development, ISSN 1083-6160, E-ISSN 1520-586X, Vol. 16, no 5, p. 1053-1063Article in journal (Refereed) Published
    Abstract [en]

    The concept of a nonresonant microwave applicator for continuous-flow organic chemistry is introduced and evaluated. The frequency of the incident microwave radiation can be adjusted between 2.4 and 2.5 GHz to optimize the energy absorbance. The temperature of the reaction is monitored by five IR sensors, and their signals can be used to automatically adjust the power output from the microwave generator. The heating of several different solvents up to 20 degrees C above the standard boiling point has been explored. Several different organic reactions have been successfully carried out using a 200 mm X (sic) 3 mm tubular borosilicate reactor and a flow between 47 and 2120 mu L/min. The microwave heating pattern was visualized with an IR camera. The transformations include palladium-catalyzed coupling reactions (oxidative Heck and Suzuki reactions), heterocyclic chemistry (oxathiazolone and Fischer indole synthesis), rearrangement (Claisen), and a Diels-Alder cycloaddition reaction. A scale-out to 57 mmol/h was performed with the Fischer indole reaction.

    Keywords
    non-resonant, microwave, Continuous-Flow, MAOS, CF-MAOS
    National Category
    Medicinal Chemistry Organic Chemistry
    Research subject
    Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-160187 (URN)10.1021/op300003b (DOI)000304129100036 ()
    Available from: 2011-10-17 Created: 2011-10-17 Last updated: 2018-01-12Bibliographically approved
1 - 19 of 19
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