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Hallberg, Anders
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Publications (10 of 82) Show all publications
Hallberg, M., Sumners, C., Steckelings, U. M. & Hallberg, A. (2018). Small-molecule AT2 receptor agonists. Medicinal research reviews (Print), 38(2), 602-624
Open this publication in new window or tab >>Small-molecule AT2 receptor agonists
2018 (English)In: Medicinal research reviews (Print), ISSN 0198-6325, E-ISSN 1098-1128, Vol. 38, no 2, p. 602-624Article, review/survey (Refereed) Published
Abstract [en]

The discovery of the first selective, small-molecule ATR receptor (AT2R) agonist compound 21 (C21) (8) that is now extensively studied in a large variety of in vitro and in vivo models is described. The sulfonylcarbamate derivative 8, encompassing a phenylthiofen scaffold is the drug-like agonist with the highest affinity for the AT2R reported to date (K-i = 0.4 nM). Structure-activity relationships (SAR), regarding different biaryl scaffolds and functional groups attached to these scaffolds and with a particular focus on the impact of various para substituents displacing the methylene imidazole group of 8, are discussed. Furthermore, the consequences of migration of the methylene imidazole group and presumed structural requirements for ligands that are aimed as AT2R agonists (e.g. 8) or AT2R antagonists (e.g. 9), respectively, are briefly addressed. A summary of the pharmacological actions of C21 (8) is also presented.

Place, publisher, year, edition, pages
John Wiley & Sons, 2018
Keywords
angiotensin II, AT2 receptor, peptidomimetics, renin-angiotensin system
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-348314 (URN)10.1002/med.21449 (DOI)000425027400006 ()28609561 (PubMedID)
Funder
Swedish Research Council
Available from: 2018-04-25 Created: 2018-04-25 Last updated: 2018-04-25Bibliographically approved
Reddy Vanga, S., Sävmarker, J., Ng, L., Larhed, M., Hallberg, M., Åqvist, J., . . . Gutiérrez-de-Terán, H. (2018). Structural Basis of Inhibition of Human Insulin-Regulated Aminopeptidase (IRAP) by Aryl Sulfonamides. ACS OMEGA, 3(4), 4509-4521
Open this publication in new window or tab >>Structural Basis of Inhibition of Human Insulin-Regulated Aminopeptidase (IRAP) by Aryl Sulfonamides
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2018 (English)In: ACS OMEGA, ISSN 2470-1343, Vol. 3, no 4, p. 4509-4521Article in journal (Refereed) Published
Abstract [en]

The insulin-regulated aminopeptidase (IRAP) is a membrane-bound zinc metallopeptidase with many important regulatory functions. It has been demonstrated that inhibition of IRAP by angiotensin IV (Ang IV) and other peptides, as well as more druglike inhibitors, improves cognition in several rodent models. We recently reported a series of aryl sulfonamides as small-molecule IRAP inhibitors and a promising scaffold for pharmacological intervention. We have now expanded with a number of derivatives, report their stability in liver microsomes, and characterize the activity of the whole series in a new assay performed on recombinant human IRAP. Several compounds, such as the new fluorinated derivative 29, present submicromolar affinity and high metabolic stability. Starting from the two binding modes previously proposed for the sulfonamide scaffold, we systematically performed molecular dynamics simulations and binding affinity estimation with the linear interaction energy method for the full compound series. The significant agreement with experimental affinities suggests one of the binding modes, which was further confirmed by the excellent correlation for binding affinity differences between the selected pair of compounds obtained by rigorous free energy perturbation calculations. The new experimental data and the computationally derived structure-activity relationship of the sulfonamide series provide valuable information for further lead optimization of novel IRAP inhibitors.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC, 2018
National Category
Biochemistry and Molecular Biology Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-358572 (URN)10.1021/acsomega.8b00595 (DOI)000434352800025 ()30023895 (PubMedID)
Funder
Swedish Research Council
Available from: 2018-09-17 Created: 2018-09-17 Last updated: 2018-09-17Bibliographically approved
Hallberg, M., Sävmarker, J. & Hallberg, A. (2017). Angiotensin Peptides as AT2 Receptor Agonists. Current protein and peptide science, 18(8), 809-818
Open this publication in new window or tab >>Angiotensin Peptides as AT2 Receptor Agonists
2017 (English)In: Current protein and peptide science, ISSN 1389-2037, E-ISSN 1875-5550, Vol. 18, no 8, p. 809-818Article, review/survey (Refereed) Published
Abstract [en]

In 2004, the first nonpeptide selective angiotensin II type 2 receptor (AT2R) agonist was reported. This nonpeptide (C21), which, exerts anti-inflammatory and antifibrotic actions in vivo, has been extensively explored and is currently in clinical trials. Subsequently, a large number of related drug-like AT2R agonists have been disclosed. Reviews that summarize known structure-activity relationships (SAR) of nonpeptide AT2R agonists have recently appeared in the literature; however, very few reviews discuss the role of angiotensin peptides as AT2R agonists. Furthermore, to date, there have been no reports focusing on the medicinal chemistry perspective of peptide AT2R agonists. In the present review, reports on linear and conformationally constrained Ang II analogues, with a focus on AT2R selective ligands that are proven to act as agonists at the AT2 receptor are summarized. The impact of truncations and macrocyclizations of Ang II analogues and of incorporation of scaffolds that mimic secondary structures into Ang II related peptides is highlighted. A survey of the efforts to transform the nonselective octapeptide Ang II to more drug-like selective AT2R agonists is presented. The relationship between the structures of the AT2R agonists and their affinity to the AT2R is briefly discussed and common pharmacophore elements of AT2R selective Ang II peptide analogues and selective nonpeptide AT2R agonists are compared.

Keywords
Angiotensin II, AT2 receptor agonist, peptide, peptidemimetic, secondary structure mimetic, bioactive conformation
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-335828 (URN)10.2174/1389203718666170203150344 (DOI)000405303000003 ()28164758 (PubMedID)
Available from: 2017-12-15 Created: 2017-12-15 Last updated: 2017-12-15Bibliographically approved
Sallander, J., Wallinder, C., Hallberg, A., Åqvist, J. & Gutierrez de Teran, H. (2016). Structural determinants of subtype selectivity and functional activity of angiotensin II receptors. Bioorganic & Medicinal Chemistry Letters, 26(4), 1355-1359
Open this publication in new window or tab >>Structural determinants of subtype selectivity and functional activity of angiotensin II receptors
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2016 (English)In: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 26, no 4, p. 1355-1359Article in journal (Refereed) Published
Abstract [en]

Agonists of the angiotensin II receptor type 2 (AT(2)), a G-protein coupled receptor, promote tissue protective effects in cardiovascular and renal diseases, while antagonists reduce neuropathic pain. We here report detailed molecular models that explain the AT(2) receptor selectivity of our recent series of non-peptide ligands. In addition, minor structural changes of these ligands that provoke different functional activity are rationalized at a molecular level, and related to the selectivity for the different receptor conformations. These findings should pave the way to structure based drug discovery of AT(2) receptor ligands.

Keywords
Angiotensin receptors, Conformational selection, Molecular docking, Homology modeling, Ligand interaction
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-279553 (URN)10.1016/j.bmcl.2015.10.084 (DOI)000369377700052 ()26810314 (PubMedID)
Funder
Swedish Research CouncileSSENCE - An eScience Collaboration
Available from: 2016-03-02 Created: 2016-03-02 Last updated: 2018-01-10Bibliographically approved
Pelcman, B., Sanin, A., Nilsson, P., No, K., Schaal, W., Öhrman, S., . . . Claesson, H.-E. (2015). 3-Substituted pyrazoles and 4-substituted triazoles as inhibitors of human 15-lipoxygenase-1. Bioorganic & medicinal chemistry letters, 25(15), 3024-3029
Open this publication in new window or tab >>3-Substituted pyrazoles and 4-substituted triazoles as inhibitors of human 15-lipoxygenase-1
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2015 (English)In: Bioorganic & medicinal chemistry letters, ISSN 1464-3405, Vol. 25, no 15, p. 3024-3029Article in journal (Refereed) Published
Abstract [en]

Investigation of 1N-substituted pyrazole-3-carboxanilides as 15-lipoxygenase-1 (15-LOX-1) inhibitors demonstrated that the 1N-substituent was not essential for activity or selectivity. Additional halogen substituents on the pyrazole ring, however, increased activity. Further development led to triazole-4-carboxanilides and 2-(3-pyrazolyl) benzoxazoles, which are potent and selective 15-LOX-1 inhibitors.

National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-256043 (URN)10.1016/j.bmcl.2015.05.004 (DOI)000356101700029 ()26037322 (PubMedID)
Available from: 2015-06-22 Created: 2015-06-22 Last updated: 2018-03-05Bibliographically approved
Villela, D., Leonhardt, J., Patel, N., Joseph, J., Kirsch, S., Hallberg, A., . . . Steckelings, U. M. (2015). Angiotensin type 2 receptor (AT2R) and receptor Mas: a complex liaison. Clinical Science, 128(4), 227-234
Open this publication in new window or tab >>Angiotensin type 2 receptor (AT2R) and receptor Mas: a complex liaison
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2015 (English)In: Clinical Science, ISSN 0143-5221, E-ISSN 1470-8736, Vol. 128, no 4, p. 227-234Article, review/survey (Refereed) Published
Abstract [en]

The angiotensin type 2 receptor (AT2R) and the receptor Mas are components of the protective arms of the renin-angiotensin system (RAS), i.e. they both mediate tissue protective and regenerative actions. The spectrum of actions of these two receptors and their signalling mechanisms display striking similarities. Moreover, in some instances, antagonists for one receptor are able to inhibit the action of agonists for the respective other receptor. These observations suggest that there may be a functional or even physical interaction of both receptors. This article discusses potential mechanisms underlying the phenomenon of blockade of angiotensin-(1-7) [Ang-(1-7)] actions by AT2R antagonists and vice versa. Such mechanisms may comprise dimerization of the receptors or dimerization-independent mechanisms such as lack of specificity of the receptor ligands used in the experiments or involvement of the Ang-(1-7) metabolite alamandine and its receptor MrgD in the observed effects. We conclude that evidence for a functional interaction of both receptors is strong, but that such an interaction may be species- and/or tissue-specific and that elucidation of the precise nature of the interaction is only at the very beginning.

National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-241212 (URN)10.1042/CS20130515 (DOI)000349364500001 ()25328009 (PubMedID)
Available from: 2015-01-08 Created: 2015-01-08 Last updated: 2018-01-11Bibliographically approved
Mohell, N., Alfredsson, J., Fransson, A., Uustalu, M., Bystrom, S., Gullbo, J., . . . Wiman, K. G. (2015). APR-246 overcomes resistance to cisplatin and doxorubicin in ovarian cancer cells. Cell Death and Disease, 6, Article ID e1794.
Open this publication in new window or tab >>APR-246 overcomes resistance to cisplatin and doxorubicin in ovarian cancer cells
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2015 (English)In: Cell Death and Disease, ISSN 2041-4889, E-ISSN 2041-4889, Vol. 6, article id e1794Article in journal (Refereed) Published
Abstract [en]

Two main causes of platinum resistance are mutation in the tumor suppressor gene TP53 and drug-induced increase in intracellular glutathione concentration. Mutations in TP53 occur in about 50% of human tumors. APR-246 (PRIMA-1(MET)) is the first clinical-stage compound that reactivates mutant p53 and induces apoptosis. APR-246 is a prodrug that is converted to the active compound methylene quinuclidinone (MQ), a Michael acceptor that binds to cysteine residues in mutant p53 and restores its wildtype conformation. Here, we show that MQ also binds to cysteine in glutathione, thus decreasing intracellular free glutathione concentration. We also show that treatment with APR-246 completely restores the cisplatin and doxorubicin sensitivity to p53-mutant drug-resistant ovarian cancer cells. We propose that this unique ability of APR-246/MQ to bind to cysteines in both mutant p53 and glutathione has a key role in the resensitization as well as in the outstanding synergistic effects observed with APR-246 in combination with platinum compounds in ovarian cancer cell lines and primary cancer cells. However, MQ binding to cysteines in other targets, for example, thioredoxin reductase, may contribute as well. Strong synergy was also observed with the DNA-damaging drugs doxorubicin and gemcitabine, while additive effects were found with the taxane docetaxel. Our results provide a strong rationale for the ongoing clinical study with APR-246 in combination with platinum-based therapy in patients with p53-mutant recurrent high-grade serous (HGS) ovarian cancer. More than 96% of these patients carry TP53 mutations. Combined treatment with APR-246 and platinum or other DNA-damaging drugs could allow dramatically improved therapy of a wide range of therapy refractory p53 mutant tumors.

National Category
Cell Biology
Identifiers
urn:nbn:se:uu:diva-259117 (URN)10.1038/cddis.2015.143 (DOI)000357514700020 ()26086967 (PubMedID)
Available from: 2015-07-28 Created: 2015-07-27 Last updated: 2017-12-04Bibliographically approved
Valero-Esquitino, V., Lucht, K., Namsolleck, P., Monnet-Tschudi, F., Stubbe, T., Lucht, F., . . . Steckelings, U. M. (2015). Direct angiotensin type 2 receptor (AT2R) stimulation attenuates T-cell and microglia activation and prevents demyelination in experimental autoimmune encephalomyelitis in mice. Clinical Science, 128(2), 95-109
Open this publication in new window or tab >>Direct angiotensin type 2 receptor (AT2R) stimulation attenuates T-cell and microglia activation and prevents demyelination in experimental autoimmune encephalomyelitis in mice
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2015 (English)In: Clinical Science, ISSN 0143-5221, E-ISSN 1470-8736, Vol. 128, no 2, p. 95-109Article in journal (Refereed) Published
Abstract [en]

In the present study, we evaluated stimulation of the angiotensin type 2 receptor (AT2R) by the selective non-peptide agonist Compound 21 (C21) as a novel therapeutic concept for the treatment of multiple sclerosis using the model of experimental autoimmune encephalomyelitis (EAE) in mice. C57BL-6 mice were immunized with myelin-oligodendrocyte peptide and treated for 4 weeks with C21 (0.3 mg/kg/day i.p.). Potential effects on myelination, microglia and T-cell composition were estimated by immunostaining and FACS analyses of lumbar spinal cords. The in vivo study was complemented by experiments in aggregating brain cell cultures and microglia in vitro. In the EAE model, treatment with C21 ameliorated microglia activation and decreased the number of total T-cells and CD4+ T-cells in the spinal cord. Fluorescent myelin staining of spinal cords further revealed a significant reduction in EAE-induced demyelinated areas in lumbar spinal cord tissue after AT2R stimulation. C21-treated mice had a significantly better neurological score than vehicle-treated controls. In aggregating brain cell cultures challenged with lipopolysaccharide (LPS) plus interferon-γ (IFNγ), AT2R stimulation prevented demyelination, accelerated re-myelination and reduced the number of microglia. Cytokine synthesis and nitric oxide production by microglia in vitro were significantly reduced after C21 treatment. These results suggest that AT2R stimulation protects the myelin sheaths in autoimmune central nervous system inflammation by inhibiting the T-cell response and microglia activation. Our findings identify the AT2R as a potential new pharmacological target for demyelinating diseases such as multiple sclerosis.

National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-241213 (URN)10.1042/CS20130601 (DOI)000349363600003 ()25052203 (PubMedID)
Available from: 2015-01-08 Created: 2015-01-08 Last updated: 2018-01-11Bibliographically approved
Pelcman, B., Sanin, A., Nilsson, P., Schaal, W., Olofsson, K., Krog-Jensen, C., . . . Claesson, H.-E. (2015). N-Substituted pyrazole-3-carboxamides as inhibitors of human 15-lipoxygenase. Bioorganic & medicinal chemistry letters, 25(15), 3017-3023
Open this publication in new window or tab >>N-Substituted pyrazole-3-carboxamides as inhibitors of human 15-lipoxygenase
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2015 (English)In: Bioorganic & medicinal chemistry letters, ISSN 1464-3405, Vol. 25, no 15, p. 3017-3023Article in journal (Refereed) Published
Abstract [en]

High-throughput screening was used to find selective inhibitors of human 15-lipoxygenase-1 (15-LOX-1). One hit, a 1-benzoyl substituted pyrazole-3-carboxanilide (1a), was used as a starting point in a program to develop potent and selective 15-LOX-1 inhibitors.

National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-256045 (URN)10.1016/j.bmcl.2015.05.007 (DOI)000356101700028 ()26037319 (PubMedID)
Available from: 2015-06-22 Created: 2015-06-22 Last updated: 2018-03-05Bibliographically approved
Leblanc, S., Battista, M.-C., Noll, C., Hallberg, A., Gallo-Payet, N., Carpentier, A. C., . . . Baillargeon, J.-P. (2014). Angiotensin II Type 2 Receptor Stimulation Improves Fatty Acid Ovarian Uptake and Hyperandrogenemia in an Obese Rat Model of Polycystic Ovary Syndrome. Endocrinology, 155(9), 3684-3693
Open this publication in new window or tab >>Angiotensin II Type 2 Receptor Stimulation Improves Fatty Acid Ovarian Uptake and Hyperandrogenemia in an Obese Rat Model of Polycystic Ovary Syndrome
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2014 (English)In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 155, no 9, p. 3684-3693Article in journal (Refereed) Published
Abstract [en]

Polycystic ovary syndrome (PCOS) is mainly defined by hyperandrogenism but is also characterized by insulin resistance (IR). Studies showed that overexposure of nonadipose tissues to nonesterified fatty acids (NEFA) may explain both IR and hyperandrogenism. Recent studies indicate that treatment with an angiotensin II type 2 receptor (AT2R)-selective agonist improves diet-induced IR. We thus hypothesized that PCOS hyperandrogenism is triggered by ovarian NEFA overexposure and is improved after treatment with an AT2R agonist. Experiments were conducted in 12-week-old female JCR:LA-cp/cp rats, which are characterized by visceral obesity, IR, hyperandrogenism, and polycystic ovaries. Control JCR:LA +/? rats have a normal phenotype. Rats were treated for 8 days with saline or the selective AT2R agonist C21/M24 and then assessed for: 1) fasting testosterone, NEFA, and insulin levels; and 2) an iv 14(R,S)-[F-18]fluoro-6-thia-heptadecanoic acid test to determine NEFA ovarian tissue uptake (Km). Compared with controls, saline-treated PCOS/cp rats displayed higher insulin (100 vs 5.6 mu U/mL), testosterone (0.12 vs 0.04 nmol/L), NEFA (0.98 vs 0.48 mmol/L), and Km (20.7 vs 12.9 nmol/g.min) (all P < .0001). In PCOS/cp rats, C21/M24 did not significantly improve insulin or NEFA but normalized testosterone (P = .004) and Km(P = .009), which were strongly correlated together in all PCOS/cp rats (rho = 0.74, P = .009). In conclusion, in an obese PCOS rat model, ovarian NEFA uptake and testosterone levels are strongly associated and are both significantly reduced after short-term C21/M24 therapy. These findings provide new information on the role of NEFA in PCOS hyperandrogenemia and suggest a potential role for AT2R agonists in the treatment of PCOS.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-235337 (URN)10.1210/en.2014-1185 (DOI)000342344300044 ()
Available from: 2014-11-03 Created: 2014-10-30 Last updated: 2017-12-05Bibliographically approved
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