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Sköld, Christian
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Publications (10 of 31) Show all publications
Wallinder, C., Sköld, C., Sundholm, S., Guimond, M.-O., Yahiaoui, S., Lindeberg, G., . . . Alterman, M. (2019). High affinity rigidified AT(2) receptor ligands with indane scaffolds. MedChemComm, 10(12), 2146-2160
Open this publication in new window or tab >>High affinity rigidified AT(2) receptor ligands with indane scaffolds
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2019 (English)In: MedChemComm, ISSN 2040-2503, E-ISSN 2040-2511, Vol. 10, no 12, p. 2146-2160Article in journal (Refereed) Published
Abstract [en]

Rigidification of the isobutyl side chain of drug-like AT(2) receptor agonists and antagonists that are structurally related to the first reported selective AT(2) receptor agonist 1 (C21) delivered bioactive indane derivatives. Four enantiomer pairs were synthesized and the enantiomers were isolated in an optical purity >99%. The enantiomers 7a, 7b, 8a, 8b, 9a, 9b, 10a and 10b bind to the AT(2) receptor with moderate (K-i = 54-223 nM) to high affinity (K-i = 2.2-7.0 nM). The enantiomer with positive optical rotation (+) exhibited the highest affinity at the receptor. The indane derivatives 7b and 10a are among the most potent AT(2) receptor antagonists reported so far. As illustrated by the enantiomer pairs 7a/b and 10a/b, an alteration at the stereogenic center has a pronounced impact on the activation process of the AT(2) receptor, and can convert agonists to antagonists and vice versa.

Place, publisher, year, edition, pages
ROYAL SOC CHEMISTRY, 2019
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-402229 (URN)10.1039/c9md00402e (DOI)000502767000012 ()
Funder
Swedish Research CouncilSwedish Foundation for Strategic Research Knut and Alice Wallenberg Foundation
Available from: 2020-01-17 Created: 2020-01-17 Last updated: 2020-01-17Bibliographically approved
Tomberg, A., Muratore, M. E., Johansson, M. J., Terstiege, I., Sköld, C. & Norrby, P.-O. (2019). Relative Strength of Common Directing Groups in Palladium-Catalyzed Aromatic C-H Activation. ISCIENCE, 20, 373-+
Open this publication in new window or tab >>Relative Strength of Common Directing Groups in Palladium-Catalyzed Aromatic C-H Activation
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2019 (English)In: ISCIENCE, ISSN 2589-0042, Vol. 20, p. 373-+Article in journal (Refereed) Published
Abstract [en]

Efficient functionalization of C-H bonds can be achieved using transition metal catalysts, such as Pd(OAc)(2). To better control the regioselectivity in these reactions, some functional groups on the substrate may be used as directing groups, guiding the reactivity to an ortho position. Herein, we describe amethodology to score the relative strength of such directing groups in palladium-catalyzed aromatic C-H activation. The results have been collected into a scale that serves to predict the regioselectivity on molecules with multiple competing directing groups. We demonstrate that this scale yields accurate predictions on over a hundred examples, taken from the literature. In addition to the regioselectivity prediction on complex molecules, the knowledge of the relative strengths of directing groups can also be used to work with new combinations of functionalities, exploring uncharted chemical space.

Place, publisher, year, edition, pages
CELL PRESS, 2019
National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-397315 (URN)10.1016/j.isci.2019.09.035 (DOI)000493388000029 ()31614320 (PubMedID)
Available from: 2019-11-25 Created: 2019-11-25 Last updated: 2019-11-25Bibliographically approved
Eriksson, J., Roy, T., Sawadjoon, S., Bachmann, K., Sköld, C., Larhed, M., . . . Odell, L. R. (2019). Synthesis and preclinical evaluation of the CRTH2 antagonist [11C]MK-7246 as a novel PET tracer and potential surrogate marker for pancreatic beta-cell mass. Nuclear Medicine and Biology, 71, 1-10
Open this publication in new window or tab >>Synthesis and preclinical evaluation of the CRTH2 antagonist [11C]MK-7246 as a novel PET tracer and potential surrogate marker for pancreatic beta-cell mass
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2019 (English)In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 71, p. 1-10Article in journal (Refereed) Published
Abstract [en]

Introduction: MK-7246 is a potent and selective antagonist for chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). Within the pancreas CRTH2 is selectively expressed in pancreatic β-cells where it is believed to play a role in insulin release. Reduction in β-cell mass and insufficient insulin secretion in response to elevated blood glucose levels is a hallmark for type 1 and type 2 diabetes. Reported here is the synthesis of [11C]MK-7246 and initial preclinical evaluation towards CRTH2 imaging. The aim is to develop a method to quantify β-cell mass with PET and facilitate non-invasive studies of disease progression in individuals with type 2 diabetes.

Methods: The precursor N-desmethyl-O-methyl MK-7246 was synthesized in seven steps and subjected to methylation with [11C]methyl iodide followed by hydrolysis to obtain [11C]MK-7246 labelled in the N-methyl position. Preclinical evaluation included in vitro radiography and immune-staining performed in human pancreatic biopsies. Biodistribution studies were performed in rat by PET-MRI and in pig by PET-CT imaging. The specific tracer uptake was examined in pig by scanning before and after administration of MK-7246 (1 mg/kg). Predicted dosimetry of [11C]MK-7246 in human males was estimated based on the biodistribution in rat.

Results: [11C]MK-7246 was obtained with activities sufficient for the current investigations (270±120 MBq) and a radiochemical purity of 93±2%. The tracer displayed focal binding in areas with insulin positive islet of Langerhans in human pancreas sections. Baseline uptake in pig was significantly reduced in CRTH2-rich areas after administration of MK-7246; pancreas (66% reduction) and spleen (88% reduction). [11C]MK-7246 exhibited a safe human predicted dosimetry profile as extrapolated from the rat biodistribution data.

Conclusions: Initial preclinical in vitro and in vivo evaluation of [11C]MK-7246 show binding and biodistribution properties suitable for PET imaging of CRTH2. Further studies are warranted to assess its potential in β-cell mass imaging and CRTH2 drug development.

National Category
Organic Chemistry Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-381559 (URN)10.1016/j.nucmedbio.2019.04.002 (DOI)000475837000001 ()
Funder
Swedish Research Council, 2018-05133Knut and Alice Wallenberg FoundationSwedish Child Diabetes FoundationGöran Gustafsson Foundation for Research in Natural Sciences and Medicine
Available from: 2019-04-11 Created: 2019-04-11 Last updated: 2019-09-13Bibliographically approved
Skogh, A., Lesniak, A., Sköld, C., Karlgren, M., Gaugaz, F. Z., Svensson, R., . . . Johansson, A. (2018). An imidazole based H-Phe-Phe-NH2 peptidomimetic with anti-allodynic effect in spared nerve injury mice. Bioorganic & Medicinal Chemistry Letters, 28(14), 2446-2450
Open this publication in new window or tab >>An imidazole based H-Phe-Phe-NH2 peptidomimetic with anti-allodynic effect in spared nerve injury mice
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2018 (English)In: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 28, no 14, p. 2446-2450Article in journal (Refereed) Published
Abstract [en]

The dipeptide amide H-Phe-Phe-NH2 (1) that previously was identified as a ligand for the substance P 1-7 (SP1-7) binding site exerts intriguing results in animal models of neuropathic pain after central but not after peripheral administration. The dipeptide 1 is derived from stepwise modifications of the anti-nociceptive heptapeptide SP1-7 and the tetrapeptide endomorphin-2 that is also binding to the SP1-7 site. We herein report a strong anti-allodynic effect of a new H-Phe-Phe-NH2 peptidomimetic (4) comprising an imidazole ring as a bioisosteric element, in the spare nerve injury (SNI) mice model after peripheral administration. Peptidomimetic 4 was stable in plasma, displayed a fair membrane permeability and a favorable neurotoxic profile. Moreover, the effective dose (ED50) of 4 was superior as compared to gabapentin and morphine that are used in clinic.

National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-343682 (URN)10.1016/j.bmcl.2018.06.009 (DOI)000438467200020 ()29929882 (PubMedID)
Funder
Swedish Research Council, 9459
Note

Title in dissertation reference list: An Imidazole-Based H-Phe-Phe-NH2 Peptidomimetic with Anti-Allodynic Effect in Spared Nerve Injury Mice and without Neurotoxic Liability

Available from: 2018-02-28 Created: 2018-02-28 Last updated: 2018-09-24Bibliographically approved
Sawant, R. T., Stevens, M. Y., Sköld, C. & Odell, L. R. (2016). Microwave-Assisted Branching Cascades: A Route to Diverse 3,4-Dihydroquinazolinone-Embedded Polyheterocyclic Scaffolds. Organic Letters, 18(20), 5392-5395
Open this publication in new window or tab >>Microwave-Assisted Branching Cascades: A Route to Diverse 3,4-Dihydroquinazolinone-Embedded Polyheterocyclic Scaffolds
2016 (English)In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 18, no 20, p. 5392-5395Article in journal (Refereed) Published
Abstract [en]

A novel metal-free microwave-assisted branching cascades strategy for the efficient synthesis of 3,4-dihydro-quinazolinone-embedded polyheterocyclic scaffolds is reported. Starting from in situ generated key N-acyliminium ion precursors, 12 distinct and skeletally diverse polycyclic frameworks were accessed in a single step/pot via adjustment of the nucleophile(s) and reaction conditions. Postcascade functionalization of these compounds was also demonstrated, proving the utility of this method in accessing structurally diverse chemical entities.

National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-308641 (URN)10.1021/acs.orglett.6b02774 (DOI)000386187300052 ()27726402 (PubMedID)
Available from: 2016-11-30 Created: 2016-11-29 Last updated: 2018-01-13Bibliographically approved
Belfrage, A. K., Gising, J., Svensson, F., Åkerblom, E., Sköld, C. & Sandström, A. (2015). Efficient and Selective Palladium-Catalysed C-3 Urea Couplings to 3,5-Dichloro-2(1H)-pyrazinones. European Journal of Organic Chemistry (5), 978-986
Open this publication in new window or tab >>Efficient and Selective Palladium-Catalysed C-3 Urea Couplings to 3,5-Dichloro-2(1H)-pyrazinones
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2015 (English)In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, no 5, p. 978-986Article in journal (Refereed) Published
Abstract [en]

The development of a robust palladium-catalysed urea N-arylation protocol to install various ureas at the 3-position of the 2(1H)-pyrazinone scaffold is described. The method involves Pd(OAc)2 in combination with bidentate ligands, xantphos [4,5-bis(diphenylphosphino)-9,9-dimethylxanthene] in particular, and resulted in good to excellent coupling yields of aliphatic, aromatic, and sterically hindered ureas. Furthermore, the C-3 chlorine was shown to be selectively displaced in the presence of aryl halide ureas, and this finding was supported by density functional theory (DFT) calculations. This allows further diversification of the scaffold for the production of compound libraries. Overall, the protocol facilitates further exploitation of pyrazinones as beta-sheet-inducing scaffolds in the development of sophisticated peptidomimetics/protease inhibitors. This is exemplified here by the synthesis of a new pyrazinone-based hepatitis C virus (HCV) NS3 protease inhibitor.

National Category
Organic Chemistry
Research subject
Chemistry with specialization in Organic Chemistry; Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-243254 (URN)10.1002/ejoc.201403405 (DOI)000349391700009 ()
Available from: 2015-02-06 Created: 2015-02-06 Last updated: 2017-12-04Bibliographically approved
Lindh, M., Svensson, F., Schaal, W., Zhang, J., Sköld, C., Brandt, P. & Karlén, A. (2015). Toward a Benchmarking Data Set Able to Evaluate Ligand- and Structure-based Virtual Screening Using Public HTS Data. Journal of Chemical Information and Modeling, 55(2), 343-353
Open this publication in new window or tab >>Toward a Benchmarking Data Set Able to Evaluate Ligand- and Structure-based Virtual Screening Using Public HTS Data
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2015 (English)In: Journal of Chemical Information and Modeling, ISSN 1549-9596, Vol. 55, no 2, p. 343-353Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2015
National Category
Structural Biology Pharmaceutical Chemistry
Research subject
Chemistry with specialization in Bioorganic Chemistry
Identifiers
urn:nbn:se:uu:diva-248018 (URN)10.1021/ci5005465 (DOI)000349943100014 ()25564966 (PubMedID)
Available from: 2015-03-26 Created: 2015-03-26 Last updated: 2018-03-05Bibliographically approved
Svensson, F., Engen, K., Lundbäck, T., Larhed, M. & Sköld, C. (2015). Virtual Screening for Transition State Analogue Inhibitors of IRAP Based on Quantum Mechanically Derived Reaction Coordinates. Journal of Chemical Information and Modeling, 55(9), 1984-1993
Open this publication in new window or tab >>Virtual Screening for Transition State Analogue Inhibitors of IRAP Based on Quantum Mechanically Derived Reaction Coordinates
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2015 (English)In: Journal of Chemical Information and Modeling, ISSN 1549-960X, Vol. 55, no 9, p. 1984-1993Article in journal (Refereed) Published
Abstract [en]

Transition state- and high energy intermediate mimetics have the potential to be very potent enzyme inhibitors. In this study a model of peptide hydrolysis in the active site of insulin-regulated aminopeptidase (IRAP) was developed using density functional theory calculations and the cluster approach. The 3D structure models of the reaction coordinates were used for virtual screening to obtain new chemical starting points for IRAP inhibitors. This mechanism-based virtual screening process managed to identify several known peptidase inhibitors from a library of over five million compounds and biological testing identified one compound not previously reported as an IRAP inhibitor. This novel methodology for virtual screening is a promising approach to identify new inhibitors mimicking key transition states or intermediates of an enzymatic reaction.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2015
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-259442 (URN)10.1021/acs.jcim.5b00359 (DOI)000362056900018 ()26252078 (PubMedID)
Funder
Carl Tryggers foundation Swedish Research Council
Available from: 2015-08-05 Created: 2015-08-04 Last updated: 2018-01-11Bibliographically approved
Borhade, S. R., Rosenström, U., Sävmarker, J., Lundbäck, T., Jenmalm-Jensen, A., Sigmundsson, K., . . . Hallberg, M. (2014). Inhibition of Insulin-Regulated Aminopeptidase (IRAP) by Arylsulfonamides. ChemistryOpen, 3(6), 256-263
Open this publication in new window or tab >>Inhibition of Insulin-Regulated Aminopeptidase (IRAP) by Arylsulfonamides
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2014 (English)In: ChemistryOpen, ISSN 2191-1363, Vol. 3, no 6, p. 256-263Article in journal (Refereed) Published
Abstract [en]

The inhibition of insulin-regulated aminopeptidase (IRAP, EC 3.4.11.3) by angiotenesin IV is known to improve memory and learning in rats. Screening 10 500 low-molecular-weight compounds in an enzyme inhibition assay with IRAP from Chinese Hamster Ovary (CHO) cells provided an arylsulfonamide (N-(3-(1H-tetrazol-5-yl)phenyl)-4-bromo-5-chlorothiophene-2-sulfonamide), comprising a tetrazole in the meta position of the aromatic ring, as a hit. Analogues of this hit were synthesized, and their inhibitory capacities were determined. A small structure-activity relationship study revealed that the sulfonamide function and the tetrazole ring are crucial for IRAP inhibition. The inhibitors exhibited a moderate inhibitory potency with an IC50=1.1±0.5 μm for the best inhibitor in the series. Further optimization of this new class of IRAP inhibitors is required to make them attractive as research tools and as potential cognitive enhancers.

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-241194 (URN)10.1002/open.201402027 (DOI)000346598100006 ()25558444 (PubMedID)
Available from: 2015-01-08 Created: 2015-01-08 Last updated: 2018-01-11Bibliographically approved
Skillinghaug, B., Sköld, C., Behrends, M., Sävmarker, J., Rydfjord, J., Sjöberg, P. & Larhed, M. (2014). Palladium(II) catalyzed desulfitative coupling reactions of sodium aryl sulfinates and nitriles: Scope, limitations, and mechanistic studies. Paper presented at 248th National Meeting of the American-Chemical-Society (ACS), AUG 10-14, 2014, San Francisco, CA. Abstract of Papers of the American Chemical Society, 248
Open this publication in new window or tab >>Palladium(II) catalyzed desulfitative coupling reactions of sodium aryl sulfinates and nitriles: Scope, limitations, and mechanistic studies
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2014 (English)In: Abstract of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 248Article in journal, Meeting abstract (Other academic) Published
National Category
Chemical Sciences
Identifiers
urn:nbn:se:uu:diva-247868 (URN)000349167403575 ()
Conference
248th National Meeting of the American-Chemical-Society (ACS), AUG 10-14, 2014, San Francisco, CA
Available from: 2015-03-24 Created: 2015-03-24 Last updated: 2017-12-04Bibliographically approved
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