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Yngve, Ulrika
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Publications (10 of 28) Show all publications
Popova, G., Ladds, M. J. G., Johansson, L., Saleh, A., Larsson, J., Sandberg, L., . . . Lain, S. (2020). Optimization of Tetrahydroindazoles as Inhibitors of Human Dihydroorotate Dehydrogenase and Evaluation of Their Activity and In Vitro Metabolic Stability. Journal of Medicinal Chemistry, 63(8), 3915-3934
Open this publication in new window or tab >>Optimization of Tetrahydroindazoles as Inhibitors of Human Dihydroorotate Dehydrogenase and Evaluation of Their Activity and In Vitro Metabolic Stability
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2020 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 63, no 8, p. 3915-3934Article in journal (Refereed) Published
Abstract [en]

Human dihydroorotate dehydrogenase (DHODH), an enzyme in the de novo pyrimidine synthesis pathway, is a target for the treatment of rheumatoid arthritis and multiple sclerosis and is re-emerging as an attractive target for cancer therapy. Here we describe the optimization of recently identified tetrahydroindazoles (HZ) as DHODH inhibitors. Several of the HZ analogues synthesized in this study are highly potent inhibitors of DHODH in an enzymatic assay, while also inhibiting cancer cell growth and viability and activating p53-dependent transcription factor activity in a reporter cell assay. Furthermore, we demonstrate the specificity of the compounds toward the de novo pyrimidine synthesis pathway through supplementation with an excess of uridine. We also show that induction of the DNA damage marker gamma-H2AX after DHODH inhibition is preventable by cotreatment with the pancaspase inhibitor Z-VAD-FMK. Additional solubility and in vitro m etabolic stability profiling revealed compound 51 as a favorable candidate for preclinical efficacy studies.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC, 2020
National Category
Pharmaceutical Sciences Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-412296 (URN)10.1021/acs.jmedchem.9b01658 (DOI)000529170200008 ()32212728 (PubMedID)
Funder
Swedish Cancer Society, CAN 2014-702Swedish Cancer Society, CAN 2017671Swedish Childhood Cancer Foundation, TJ2014-0013Swedish Research Council, 2017-0241Swedish Research Council, 538-2013-8807
Available from: 2020-08-24 Created: 2020-08-24 Last updated: 2020-08-24Bibliographically approved
Ladds, M. J. G., van Leeuwen, I. M. M., Drummond, C. J., Chu, S., Healy, A. R., Popova, G., . . . Lain, S. (2018). A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage. Nature Communications, 9, Article ID 1107.
Open this publication in new window or tab >>A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage
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2018 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 9, article id 1107Article in journal (Refereed) Published
Abstract [en]

The development of non-genotoxic therapies that activate wild-type p53 in tumors is of great interest since the discovery of p53 as a tumor suppressor. Here we report the identification of over 100 small-molecules activating p53 in cells. We elucidate the mechanism of action of a chiral tetrahydroindazole (HZ00), and through target deconvolution, we deduce that its active enantiomer (R)-HZ00, inhibits dihydroorotate dehydrogenase (DHODH). The chiral specificity of HZ05, a more potent analog, is revealed by the crystal structure of the (R)-HZ05/DHODH complex. Twelve other DHODH inhibitor chemotypes are detailed among the p53 activators, which identifies DHODH as a frequent target for structurally diverse compounds. We observe that HZ compounds accumulate cancer cells in S-phase, increase p53 synthesis, and synergize with an inhibitor of p53 degradation to reduce tumor growth in vivo. We, therefore, propose a strategy to promote cancer cell killing by p53 instead of its reversible cell cycle arresting effect.

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-351427 (URN)10.1038/s41467-018-03441-3 (DOI)000427591600007 ()29549331 (PubMedID)
Funder
Swedish Research CouncilSwedish Cancer SocietySwedish Childhood Cancer FoundationWellcome trust, 073915NIH (National Institutes of Health), R01 CA95684
Note

Correction in: Nature Communications volume 14, Article number: 5019 (2023)

DOI: 10.1038/s41467-023-40764-2

Available from: 2018-06-01 Created: 2018-06-01 Last updated: 2023-10-24Bibliographically approved
Nordeman, P., Yngve, U., Wilking, H., Gustavsson, S. Å., Eriksson, J. & Antoni, G. (2018). Automated GMP-production of α-[11 C]methyl-L-tryptophan using a tracer production system (TPS). Journal of labelled compounds & radiopharmaceuticals, 61(14), 1106-1109
Open this publication in new window or tab >>Automated GMP-production of α-[11 C]methyl-L-tryptophan using a tracer production system (TPS)
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2018 (English)In: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 61, no 14, p. 1106-1109Article in journal (Refereed) Published
Abstract [en]

The radiosynthesis and GMP validation of [11 C]AMT for human use are described. Three consecutive batches were produced giving 940-3790 MBq (4%-17% RCY, decay corrected, based on [11 C]CO2 ) of the tracer. The molar activity at the end of synthesis was 19 to 35 GBq/μmol, the radiochemical purity was ≥98%, and the enantiomeric purity was >99%. While the synthesis method was automated using a new generation of synthesis equipment, tracer production system developed in house, the method should be readily applicable to other synthesis platforms with minor modifications.

Keywords
[11C]AMT, automation, methyl iodide, positron emission tomography, tracer production system
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-368809 (URN)10.1002/jlcr.3648 (DOI)000453709100011 ()29902836 (PubMedID)
Available from: 2018-12-07 Created: 2018-12-07 Last updated: 2019-01-15Bibliographically approved
Fang, X. T., Eriksson, J., Antoni, G., Yngve, U., Cato, L., Lannfelt, L., . . . Syvänen, S. (2017). Brain mGluR5 in mice with amyloid beta pathology studied with in vivo [(11)C]ABP688 PET imaging and ex vivo immunoblotting. Neuropharmacology, 113(Pt A), 293-300, Article ID S0028-3908(16)30459-2.
Open this publication in new window or tab >>Brain mGluR5 in mice with amyloid beta pathology studied with in vivo [(11)C]ABP688 PET imaging and ex vivo immunoblotting
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2017 (English)In: Neuropharmacology, ISSN 0028-3908, E-ISSN 1873-7064, Vol. 113, no Pt A, p. 293-300, article id S0028-3908(16)30459-2Article in journal (Refereed) Published
Abstract [en]

Alzheimer's disease (AD) is characterized by aggregation of amyloid beta (Aβ) into insoluble plaques. Intermediates, Aβ oligomers (Aβo), appear to be the mechanistic cause of disease. The de facto PET AD ligand, [(11)C]PIB, binds and visualizes Aβ plaque load, which does not correlate well with disease severity. Therefore, finding a dynamic target that changes with pathology progression in AD is of great interest. Aβo alter synaptic plasticity, inhibit long-term potentiation, and facilitate long-term depression; key mechanisms involved in memory and learning. In order to convey these neurotoxic effects, Aβo requires interaction with the metabotropic glutamate 5 receptor (mGluR5). The aim was to investigate in vivo mGluR5 changes in an Aβ pathology model using PET. Wild type C57/BL6 (wt) and AβPP transgenic mice (tg-ArcSwe), 4, 8, and 16 months old, were PET scanned with [(11)C]ABP688, which is highly specific to mGluR5, to investigate changes in mGluR5. Mouse brains were extracted postscan and mGluR5 and Aβ protofibril levels were assessed with immunoblotting and ELISA respectively. Receptor-dense brain regions (hippocampus, thalamus, and striatum) displayed higher [(11)C]ABP688 concentrations corresponding to mGluR5 expression pattern. Mice had similar uptake levels of [(11)C]ABP688 regardless of genotype or age. Immunoblotting revealed general decline in mGluR5 expression and elevated levels of mGluR5 in 16 months old tg-ArcSwe compared with wt mice. [(11)C]ABP688 could visualize mGluR5 in the mouse brain. In conclusion, mGluR5 levels were found to decrease with age and tended to be higher in tg-ArcSwe compared with wt mice, however these changes could not be quantified with PET.

Keywords
Alzheimer's disease, PET, [(11)C]ABP688, mGluR5
National Category
Geriatrics Radiology, Nuclear Medicine and Medical Imaging Neurology Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-317721 (URN)10.1016/j.neuropharm.2016.10.009 (DOI)000390502200028 ()27743932 (PubMedID)
Available from: 2017-03-17 Created: 2017-03-17 Last updated: 2018-01-13Bibliographically approved
Yngve, U., Nordeman, P., Estrada, S., Marklund, N., Auberson, Y., Machauer, R., . . . Antoni, G. (2015). Tracing BACE: Synthesis and evaluation of beta-secretase inhibitors as ligands for PET imaging. Journal of labelled compounds & radiopharmaceuticals, 58, S51-S51
Open this publication in new window or tab >>Tracing BACE: Synthesis and evaluation of beta-secretase inhibitors as ligands for PET imaging
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2015 (English)In: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 58, p. S51-S51Article in journal, Meeting abstract (Other academic) Published
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-284900 (URN)000369950200052 ()
Available from: 2016-04-19 Created: 2016-04-19 Last updated: 2017-11-30Bibliographically approved
Besidski, Y., Yngve, U., Paulsen, K., Linde, C. & Malmborg, J. (2014). Preparation of aminotriazole compounds as gamma secretase modulators useful for treatment of Aβ-related diseases.. Acturum Life Science AB, Swed. . (WO2014195322A1) .
Open this publication in new window or tab >>Preparation of aminotriazole compounds as gamma secretase modulators useful for treatment of Aβ-related diseases.
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2014 (English)Patent (Other (popular science, discussion, etc.))
Abstract [en]

The invention relates to aminotriazole compds. of formula I and pharmaceutically acceptable salts and pharmaceutical compns. thereof, as well as processes for making these compds. for use in the treatment and/or prevention of Aβ-related diseases. I [wherein A is (un)substituted 5- or 6-membered heteroaryl ring comprising at least one N; R1 is H, C1-3-alkyl, cyano, etc.; R2 is (un)substituted C1-6-alkyl, C3-7-cycloalkyl-C1-3-alkyl, heterocyclyl-C1-3-alkyl, etc.; R3 and R4 are each independently selected from H, C1-6-alkyl, (un)substituted C3-7-cycloalkyl, etc.] or pharmaceutically acceptable salts thereof are claimed and exemplified. Example compd. II was prepd. from the reaction of 3-bromo-N-(cyclopropylmethyl)-1-methyl-1H-1,2,4-triazol-5-amine with 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline dihydrochloride under Buchwald-Hartwig conditions in 26% yield. Nine compds. of I were evaluated for inhibition of Aβ formation utilizing electrochemiluminescence anal. and HEK cells expressing amyloid precursor protein (data given). [on SciFinder(R)]

Place, publisher, year, edition, pages
Acturum Life Science AB, Swed. ., 2014
Keywords
aminotriazole compd prepn gamma secretase modulator amyloid beta disease
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-270227 (URN)
Note

CAPLUS AN 2014:2052050(Patent)

Available from: 2015-12-22 Created: 2015-12-22 Last updated: 2018-01-10
Besidski, Y., Yngve, U., Paulsen, K., Linde, C., Nordvall, G., Macsari, I. & Malmborg, J. (2014). Preparation of azetidinotriazole compounds as gamma secretase modulators useful for treatment of Aβ-related diseases.. Acturum Life Science AB, Swed. . (WO2014195321A1) .
Open this publication in new window or tab >>Preparation of azetidinotriazole compounds as gamma secretase modulators useful for treatment of Aβ-related diseases.
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2014 (English)Patent (Other (popular science, discussion, etc.))
Abstract [en]

The invention relates to azetidinotriazole compds. of formula I and pharmaceutically acceptable salts and pharmaceutical compns. thereof, as well as processes for making these compds. for use in the treatment and/or prevention of Aβ-related diseases. I [wherein A is (un)substituted 5- or 6-membered heteroaryl ring comprising at least one N; R1 is H, C1-3-alkyl, cyano, etc.; R2 is (un)substituted C1-6-alkyl, C3-7-cycloalkyl-C1-3-alkyl, heterocyclyl-C1-3-alkyl, etc.; R3, R5, and R7 are each independently selected from H, (un)substituted C1-3-alkyl, C3-7-cycloalkyl, etc.; R4, R6, R8 are each independently selected from H, F, C1-3-alkyl, etc.; or R3 and R4, or R5 and R6, or R7 and R8, together with the carbon to which they are attached, form (un)substituted 3- to 7-membered satd. ring optionally contg. an O or N] or pharmaceutically acceptable salts thereof are claimed and exemplified. Example compd. II was prepd. from the reaction of III with 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline under Buchwald-Hartwig conditions in 26% yield. Nine compds. of I were evaluated for activity on Aβ formation utilizing electrochemiluminescence anal. and HEK cells expressing amyloid precursor protein (data given). [on SciFinder(R)]

Place, publisher, year, edition, pages
Acturum Life Science AB, Swed. ., 2014
Keywords
azetidinotriazole compd prepn gamma secretase modulator amyloid beta disease
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-270226 (URN)
Note

CAPLUS AN 2014:2053612(Patent)

Available from: 2015-12-22 Created: 2015-12-22 Last updated: 2018-01-10
Besidski, Y., Yngve, U., Paulsen, K., Linde, C., Macsari, I., Malmborg, J., . . . Arvidsson, P. (2014). Preparation of pyrimidinylamine compounds as gamma secretase modulators useful for treatment of Aβ-related diseases.. Acturum Life Science AB, Swed. . (WO2014195323A1) .
Open this publication in new window or tab >>Preparation of pyrimidinylamine compounds as gamma secretase modulators useful for treatment of Aβ-related diseases.
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2014 (English)Patent (Other (popular science, discussion, etc.))
Abstract [en]

The invention relates to pyrimidinylamine compds. of formula I and pharmaceutically acceptable salts and pharmaceutical compns. thereof, as well as processes for making these compds. for use in the treatment and/or prevention of Aβ-related diseases. I [wherein A is (un)substituted 5- or 6-membered heteroaryl ring comprising at least one N; R1 is H, C1-3-alkyl, cyano, etc.; R2 and R3 are each independently selected from C1-3-alkyl and fluoro-C1-3-alkyl; or R2 and R3 together with the carbon to which they are attached form a 3- to 6-membered satd. carbocyclic ring, optionally substituted with one or more fluoro substituents; R4 is C1-3-alkyl, fluoro-C1-3-alkyl, or C3-6-cycloalkyl-C1-3-alkyl; R5 is H, C1-3-alkyl, fluoro, etc.; R6 is, for example, CH3NH-, CNCH2-, or MeO-] or pharmaceutically acceptable salts thereof are claimed and exemplified. Example compd. II was prepd. from the reaction of III with 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline under Buchwald-Hartwig conditions in 77% yield. Fifty-two compds. of I were evaluated for activity on Aβ formation utilizing electrochemiluminescence anal. and HEK cells expressing amyloid precursor protein (data given). [on SciFinder(R)]

Place, publisher, year, edition, pages
Acturum Life Science AB, Swed. ., 2014
Keywords
pyrimidinylamine compd prepn gamma secretase modulator amyloid beta disease
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-270225 (URN)
Note

CAPLUS AN 2014:2054594(Patent)

Available from: 2015-12-22 Created: 2015-12-22 Last updated: 2018-01-10
Yngve, U., Paulsen, K., Macsari, I., Sundstrom, M., Santangelo, E., Linde, C., . . . Arvidsson, P. I. (2013). Triazolopyrimidinones as gamma-secretase modulators: structure-activity relationship, modulator profile, and in vivo profiling. MedChemComm, 4(2), 422-431
Open this publication in new window or tab >>Triazolopyrimidinones as gamma-secretase modulators: structure-activity relationship, modulator profile, and in vivo profiling
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2013 (English)In: MedChemComm, ISSN 2040-2503, E-ISSN 2040-2511, Vol. 4, no 2, p. 422-431Article in journal (Refereed) Published
Abstract [en]

The structure-activity relationship for a series of potent g-secretase modulators based on the 6,7-dihydro4H-[1,2,4]triazolo[1,5-a]pyrimidin-5-one scaffold is described. Furthermore, we report details regarding the modulator profile on A beta processing, as well as in vivo efficacy, for the optimized compounds.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-196029 (URN)10.1039/c2md20312j (DOI)000314311600019 ()
Available from: 2013-03-04 Created: 2013-03-04 Last updated: 2017-12-06
Macsari, I., Besidski, Y., Csjernyik, G., Nilsson, L. I., Sandberg, L., Yngve, U., . . . Arvidsson, P. I. (2012). 3-Oxoisoindoline-1-carboxamides: Potent, State-Dependent Blockers of Voltage-Gated Sodium Channel Na(V)1.7 with Efficacy in Rat Pain Models. Journal of Medicinal Chemistry, 55(15), 6866-6880
Open this publication in new window or tab >>3-Oxoisoindoline-1-carboxamides: Potent, State-Dependent Blockers of Voltage-Gated Sodium Channel Na(V)1.7 with Efficacy in Rat Pain Models
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2012 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 55, no 15, p. 6866-6880Article in journal (Refereed) Published
Abstract [en]

The voltage-gated sodium channel Na(V)1.7 is believed to be a critical mediator of pain sensation based on clinical genetic studies and pharmacological results. Clinical utility of nonselective sodium channel blockers is limited due to serious adverse drug effects. Here, we present the optimization, structure activity relationships, and in vitro and in vivo characterization of a novel series of Na(V)1.7 inhibitors based on the oxoisoindoline core. Extensive studies with focus on optimization of Na(V)1.7 potency, selectivity over Na(V)1.5, and metabolic stability properties produced several interesting oxoisoindoline carboxamides (16A, 26B, 28, 51, 60, and 62) that were further characterized. The oxoisoindoline carboxamides interacted with the local anesthetics binding site. In spite of this, several compounds showed functional selectivity versus Na(V)1.5 of more than 100-fold. This appeared to be a combination of subtype and state-dependent selectivity. Compound 28 showed concentration-dependent inhibition of nerve injury-induced ectopic in an ex vivo DRG preparation from SNL rats. Compounds 16A and 26B demonstrated concentration-dependent efficacy in preclinical behavioral pain models. The oxoisoindoline carboxamides series described here may be valuable for further investigations for pain therapeutics.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-179901 (URN)10.1021/jm300623u (DOI)000307264100019 ()
Available from: 2012-08-28 Created: 2012-08-27 Last updated: 2017-12-07
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