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Wannberg, Johan
Publications (10 of 20) Show all publications
Isaksson, R., Lindman, J., Wannberg, J., Sallander, J., Backlund, M., Baraldi, D., . . . Larhed, M. (2019). A Series of Analogues to the AT2R Prototype Antagonist C38 Allow Fine Tuning of the Previously Reported Antagonist Binding Mode. ChemistryOpen, 8(1), 114-125
Open this publication in new window or tab >>A Series of Analogues to the AT2R Prototype Antagonist C38 Allow Fine Tuning of the Previously Reported Antagonist Binding Mode
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2019 (English)In: ChemistryOpen, ISSN 2191-1363, Vol. 8, no 1, p. 114-125Article in journal (Refereed) Published
Abstract [en]

We here report on our continued studies of ligands binding tothe promising drug target angiotensin II type 2 receptor (AT2R). Two series of compounds were synthesized and investigated. The first series explored the effects of adding small substituents to the phenyl ring of the known selective nonpeptide AT2R antagonist C38, generating small but significant shifts in AT2R affinity. One compound in the first series was equipotent to C38 and showed similar kinetic solubility, and stability in both human and mouse liver microsomes. The second series was comprised of new bicyclic derivatives, amongst which one ligand exhibited a five-fold improved affinity to AT2R ascompared to C38. The majority of the compounds in the second series, including the most potent ligand, were inferior to C38 with regard to stability in both human and mouse microsomes. In contrast to our previously reported findings, ligands with shorter carbamate alkyl chains only demonstrated slightly improved stability in microsomes. Based on data presented herein, a more adequate, tentative model of the binding modes of ligand analogues to the prototype AT2R antagonist C38 is proposed, as deduced from docking redefined by molecular dynamic simulations.

National Category
Organic Chemistry Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-377050 (URN)10.1002/open.201800282 (DOI)000457433000017 ()30697513 (PubMedID)
Funder
Swedish National Infrastructure for Computing (SNIC)Swedish Research Council
Available from: 2019-02-13 Created: 2019-02-13 Last updated: 2019-04-04Bibliographically approved
Wannberg, J., Isaksson, R., Bremberg, U., Backlund, M., Sävmarker, J., Hallberg, M. & Larhed, M. (2018). A convenient transesterification method for synthesis of AT2 receptor ligands with improved stability in human liver microsomes. Bioorganic & Medicinal Chemistry Letters, 28(3), 519-522
Open this publication in new window or tab >>A convenient transesterification method for synthesis of AT2 receptor ligands with improved stability in human liver microsomes
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2018 (English)In: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 28, no 3, p. 519-522Article in journal (Refereed) Published
Abstract [en]

A series of AT2R ligands have been synthesized applying a quick, simple, and safetransesterification-type reaction whereby the sulfonyl carbamate alkyl tail ofthe selective AT2R antagonist C38 was varied. Furthermore, a limited number ofcompounds where acyl sulfonamides and sulfonyl ureas served as carboxylic acidbioisosteres were synthesized and evaluated. By reducing the size of the alkylchain of the sulfonyl carbamates, ligands 7a and 7b were identified withsignificantly improved in vitro metabolic stability in both human and mouse livermicrosomes as compared to C38 while retaining the AT2R binding affinity andAT2R/AT1R selectivity. Eight of the compounds synthesized exhibit an improvedstability in human microsomes as compared to C38.

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
AT(2)R antagonists, Angiotensin II type 2 receptor antagonists, Liver microsomes, Sulfonyl carbamates, Transesterification
National Category
Organic Chemistry Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-343592 (URN)10.1016/j.bmcl.2017.11.042 (DOI)000424285600053 ()29279275 (PubMedID)
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2018-02-28 Created: 2018-02-28 Last updated: 2019-04-04Bibliographically approved
Wannberg, J., Isaksson, R., Hallberg, M. & Larhed, M. (2017). Transcarbamoylation of sulfonyl carbamates to generate new Angiotensin II Type 2 Receptor (AT2R) ligands. Paper presented at 253rd National Meeting of the American-Chemical-Society (ACS) on Advanced Materials, Technologies, Systems, and Processes, APR 02-06, 2017, San Francisco, CA. Abstract of Papers of the American Chemical Society, 253
Open this publication in new window or tab >>Transcarbamoylation of sulfonyl carbamates to generate new Angiotensin II Type 2 Receptor (AT2R) ligands
2017 (English)In: Abstract of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 253Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
American Chemical Society (ACS), 2017
National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-377534 (URN)000430569104482 ()
Conference
253rd National Meeting of the American-Chemical-Society (ACS) on Advanced Materials, Technologies, Systems, and Processes, APR 02-06, 2017, San Francisco, CA
Available from: 2019-02-25 Created: 2019-02-25 Last updated: 2019-02-25Bibliographically approved
Kumpina, I., Isaksson, R., Sävmarker, J., Wannberg, J. & Larhed, M. (2016). Microwave Promoted Transcarbamylation Reaction of Sulfonylcarbamates under Continuous-Flow Conditions. Organic Process Research & Development, 20(2), 440-445
Open this publication in new window or tab >>Microwave Promoted Transcarbamylation Reaction of Sulfonylcarbamates under Continuous-Flow Conditions
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2016 (English)In: Organic Process Research & Development, ISSN 1083-6160, E-ISSN 1520-586X, Vol. 20, no 2, p. 440-445Article in journal (Refereed) Published
Abstract [en]

Successful conditions for the transcarbamylation/transesterification reaction of sulfonylcarbamates with alcohols by microwave heating under continuous flow conditions were developed. After optimization of the processes, two series of O-alkylsulfonylcarbamates were obtained in high yields and purities using microwave transparent borosilicate tube reactors. In order to also illustrate the usefulness of the protocol in a medicinal chemistry context, the methodology was used for the synthesis of three angiotensin II type 2 receptor ligands.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-282387 (URN)10.1021/acs.oprd.5b00323 (DOI)000370767600033 ()
Funder
EU, FP7, Seventh Framework Programme, REGPOT-CT-2013-316149-InnovaBalt
Available from: 2016-04-05 Created: 2016-04-05 Last updated: 2019-04-04Bibliographically approved
Isaksson, R., Kumpina, I., Larhed, M. & Wannberg, J. (2016). Rapid and straightforward transesterification of sulfonyl carbamates. Tetrahedron Letters, 57(13), 1476-1478
Open this publication in new window or tab >>Rapid and straightforward transesterification of sulfonyl carbamates
2016 (English)In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 57, no 13, p. 1476-1478Article in journal (Refereed) Published
Abstract [en]

A fast and convenient method for the alkoxy exchange of sulfonyl carbamates by simply heating in a chosen alkyl alcohol is described. No catalysts or additives are required. Microwave heating at 100-120 degrees C for 20-60 min resulted in good to excellent yields (53-93%) of alkyl (arylsulfonyl)carbamates where the alkyl part originates from the alcohol solvent. The developed protocol was applied to the synthesis of an angiotensin II type 2 receptor (AT2R) ligand.

Keywords
Sulfonyl carbamates, O-alkyl exchange, Transesterification, Carboxylic acid bioisosteres, AT2R ligand
National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-294300 (URN)10.1016/j.tetlet.2016.02.071 (DOI)000372690800018 ()
Funder
EU, FP7, Seventh Framework Programme, REGPOT-CT-2013-316149-InnovaBalt
Available from: 2016-05-19 Created: 2016-05-18 Last updated: 2019-04-04Bibliographically approved
Wakchaure, P. B., Bremberg, U., Wannberg, J. & Larhed, M. (2015). Synthesis of enantiopure angiotensin II type 2 receptor [AT(2)R] antagonist EMA401. Tetrahedron, 71(38), 6881-6887
Open this publication in new window or tab >>Synthesis of enantiopure angiotensin II type 2 receptor [AT(2)R] antagonist EMA401
2015 (English)In: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 71, no 38, p. 6881-6887Article in journal (Refereed) Published
Abstract [en]

We report a facile synthesis of the angiotensin II type 2 receptor antagonist EMA401, which recently passed phase II clinical trials, in high overall yield. The synthesis of the key phenylalanine intermediate involved the formation of an a-nitro cinnamic ester and its reduction followed by a Pictet-Spengler cyclization, which furnished the tetrahydroisoquinoline core structure. Next, EMA401 was separated from its enantiomer EMA402 by four recrystalizations of a diastereomeric salt in 98% ee. All steps were performed on gram scale with emphasis on avoiding column purification and using readily available low cost starting materials and reagents.

Keywords
EMA401, Angiotensin II type 2 receptor, Synthesis, Enantiopure
National Category
Chemical Sciences
Identifiers
urn:nbn:se:uu:diva-262404 (URN)10.1016/j.tet.2015.07.018 (DOI)000359874300032 ()
Available from: 2015-09-21 Created: 2015-09-15 Last updated: 2017-12-04Bibliographically approved
Engen, K., Sävmarker, J., Rosenström, U., Wannberg, J., Lundbäck, T., Jenmalm-Jensen, A. & Larhed, M. (2014). Microwave Heated Flow Synthesis of Spiro-oxindole Dihydroquinazolinone Based IRAP Inhibitors. Organic Process Research & Development, 18(11), 1582-1588
Open this publication in new window or tab >>Microwave Heated Flow Synthesis of Spiro-oxindole Dihydroquinazolinone Based IRAP Inhibitors
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2014 (English)In: Organic Process Research & Development, ISSN 1083-6160, E-ISSN 1520-586X, Vol. 18, no 11, p. 1582-1588Article in journal (Refereed) Published
Abstract [en]

A fast and convenient synthetic route towards spiro-oxindole dihydroquinazolinones as novel and drug-like insulin-regulated aminopeptidase (IRAP) inhibitors is reported. The synthesis is performed using a MW heated continuous flow system employing 200 mm X 3 mm i MW absorbing silicon carbide (SiC) or MW transparent borosilicate tubular reactors. A three-component MW-flow reaction to build up the spiro compounds (9 examples, 4087% yield), using the SiC reactor, as well as a SuzukiMiyaura cross-coupling reaction (71%), employing the borosilicate reactor, are presented with residence times down to 168 s. The continuous MW-flow routes provide a smooth and scalable synthetic methodology towards this class of IRAP inhibitors.

National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-240315 (URN)10.1021/op500237k (DOI)000345552100043 ()
Available from: 2015-01-07 Created: 2015-01-07 Last updated: 2018-01-11Bibliographically approved
Engen, K., Sävmarker, J., Lundback, T., Wannberg, J., Jenmalm-Jensen, A., Rosenström, U. & Larhed, M. (2014). Nonresonant microwave heated continuous flow synthesis in medicinal chemistry. 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 >>Nonresonant microwave heated continuous flow synthesis in medicinal chemistry
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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
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-247862 (URN)000349167402702 ()
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: 2018-01-11Bibliographically approved
Wannberg, J., Wallinder, C., Unlusoy, M., Sköld, C. & Larhed, M. (2013). One-Pot, Two-Step, Microwave-Assisted Palladium-Catalyzed Conversion of Aryl Alcohols to Aryl Fluorides via Aryl Nonaflates. Journal of Organic Chemistry, 78(8), 4184-4189
Open this publication in new window or tab >>One-Pot, Two-Step, Microwave-Assisted Palladium-Catalyzed Conversion of Aryl Alcohols to Aryl Fluorides via Aryl Nonaflates
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2013 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 78, no 8, p. 4184-4189Article in journal (Refereed) Published
Abstract [en]

A convenient procedure for converting aryl alcohols to aryl fluorides via aryl nonafluorobutylsulfonates (ArONf) is presented. Moderate to good one-pot, two-step yields were achieved by this nonaflation and microwave-assisted, palladium-catalyzed fluorination sequence. The reductive elimination step was investigated by DFT calculations to compare fluorination with chlorination, proving a larger thermodynamic driving force for the aryl fluoride product. Finally, a key aryl fluoride intermediate for the synthesis of a potent HCV NS3 protease inhibitor was smoothly prepared with the novel protocol.

National Category
Medical and Health Sciences Natural Sciences
Identifiers
urn:nbn:se:uu:diva-203361 (URN)10.1021/jo400255m (DOI)000319708300024 ()
Available from: 2013-07-09 Created: 2013-07-09 Last updated: 2017-12-06Bibliographically approved
Mahalingam, A. K., Axelsson, L., Ekegren, J. K., Wannberg, J., Kihlström, J., Unge, T., . . . Hallberg, A. (2010). HIV-1 Protease Inhibitors with a Transition-State Mimic Comprising a Tertiary Alcohol: Improved Antiviral Activity in Cells. Journal of Medicinal Chemistry, 53(2), 607-615
Open this publication in new window or tab >>HIV-1 Protease Inhibitors with a Transition-State Mimic Comprising a Tertiary Alcohol: Improved Antiviral Activity in Cells
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2010 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 53, no 2, p. 607-615Article in journal (Refereed) Published
Abstract [en]

By a small modification in the core structure of the previously reported series of HIV-1 protease inhibitors that encompasses a tertiary alcohol as part of the transition-state mimicking scaffold, up to 56 times more potent compounds were obtained exhibiting EC50 values down to 3 nM. Three of the inhibitors also displayed excellent activity against selected resistant isolates of HIV-1. The synthesis of 25 new and optically pure HIV-1 protease inhibitors is reported, along with methods for elongation of the inhibitor Pl' side chain using microwave-accelerated, palladium-catalyzed cross-coupling reactions, the biological evaluation, and X-ray data obtained from one of the most potent analogues cocrystallized with both the wild type and the L63P, V82T, 184 V mutant of the HIV-1 protease.

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-137907 (URN)10.1021/jm901165g (DOI)000273672100007 ()
Available from: 2010-12-17 Created: 2010-12-16 Last updated: 2018-01-12Bibliographically approved
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