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Dahlgren, Anders
Publications (9 of 9) Show all publications
Sandgren, V., Belda, O., Kvarnström, I., Lindberg, J., Samuelsson, B. & Dahlgren, A. (2015). Design and Synthesis of Novel Arylketo-containing P1-P3 Linked Macro-cyclic BACE-1 Inhibitors. Open Medicinal Chemistry Journal, 9, 13-26
Open this publication in new window or tab >>Design and Synthesis of Novel Arylketo-containing P1-P3 Linked Macro-cyclic BACE-1 Inhibitors
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2015 (English)In: Open Medicinal Chemistry Journal, ISSN 1874-1045, Vol. 9, p. 13-26Article in journal (Refereed) Published
Abstract [en]

A series of arylketo-containing P1-P3 linked macrocyclic BACE-1 inhibitors were designed, synthesized, and compared with compounds with a previously known and extensively studied corresponding P2 isophthalamide moiety with the aim to improve on permeability whilst retaining the enzyme- and cell-based activities. Several inhibitors displayed substantial increases in Caco-2 cell-based permeability compared to earlier synthesized inhibitors and notably also with retained activities, showing that this approach might yield BACE-1 inhibitors with improved properties.

Place, publisher, year, edition, pages
Bussum, Netherlands: Bentham Open, 2015
Keywords
Alzheimer’s disease, BACE-1 inhibition, cellular permeability, macrocycles, ring-closing metathesis, X-ray structure
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:liu:diva-120598 (URN)10.2174/1874104501509010013 (DOI)25937848 (PubMedID)
Available from: 2015-08-18 Created: 2015-08-18 Last updated: 2018-01-11Bibliographically approved
Sandgren, V., Bäck, M., Kvarnström, I. & Dahlgren, A. (2013). Design and synthesis of hydroxyethylene-based BACE-1 inhibitors incorporating extended P1 substituents. Open Medicinal Chemistry Journal, 7, 1-15
Open this publication in new window or tab >>Design and synthesis of hydroxyethylene-based BACE-1 inhibitors incorporating extended P1 substituents
2013 (English)In: Open Medicinal Chemistry Journal, ISSN 1874-1045, Vol. 7, p. 1-15Article in journal (Refereed) Published
Abstract [en]

Novel BACE-1 inhibitors with a hydroxyethylene central core have been  developed. Modified P1´ and extended P1 substituents were incorporated with the aim to explore potential interactions with the S1´ and the S1-S3 pocket, respectively, of BACE-1. Inhibitors were identified displaying IC50 values in the nanomolar range, i.e., 69 nM for the most potent compound. Possible inhibitor interactions with the enzyme are also discussed.

Place, publisher, year, edition, pages
Bussum, Netherlands: Bentham Open, 2013
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-76171 (URN)10.2174/1874104501307010001 (DOI)
Available from: 2012-03-29 Created: 2012-03-29 Last updated: 2017-12-07Bibliographically approved
Sandgren, V., Agback, T., Johansson, P.-O., Lindberg, J., Kvarnström, I., Samuelsson, B., . . . Dahlgren, A. (2012). Highly potent macrocyclic BACE-1 inhibitors incorporating a hydroxyethylamine core: Design, synthesis and X-ray crystal structures of enzyme inhibitor complexes. Bioorganic & Medicinal Chemistry, 29(14), 4377-4389
Open this publication in new window or tab >>Highly potent macrocyclic BACE-1 inhibitors incorporating a hydroxyethylamine core: Design, synthesis and X-ray crystal structures of enzyme inhibitor complexes
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2012 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 29, no 14, p. 4377-4389Article in journal (Refereed) Published
Abstract [en]

A series of P1-P3 linked macrocyclic BACE-1 inhibitors containing a hydroxyethylamine (HEA) isostere scaffold has been synthesized. All inhibitors comprise a toluene or N-phenylmethanesulfonamide P2 moiety. Excellent BACE-1 potencies, both in enzymatic and cell-based assays, were observed in this series of target compounds, with the best candidates displaying cell-based IC50 values in the low nanomolar range. As an attempt to improve potency, a phenyl substituent aiming at the S3 subpocket was introduced in the macrocyclic ring. X-ray analyses were performed on selected compounds, and enzyme-inhibitor interactions are discussed.

Place, publisher, year, edition, pages
Elsevier, 2012
Keywords
Alzheimer’s disease; BACE-1 inhibition; Macrocycles; Hydroxyethylamine (HEA) isostere
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-76172 (URN)10.1016/j.bmc.2012.05.039 (DOI)000305952500023 ()
Note

On the day of the defence day the status of this article was Manuscript.

Available from: 2012-03-29 Created: 2012-03-29 Last updated: 2017-12-07Bibliographically approved
Dahlgren, A., Kvarnström, I., Vrang, L., Hamelink, E., Hallberg, A., Rosenquist, A. & Samuelsson, B. (2003). New inhibitors of the malaria aspartyl proteases plasmepsin I and II. Bioorganic & Medicinal Chemistry, 11(16), 3423-3437
Open this publication in new window or tab >>New inhibitors of the malaria aspartyl proteases plasmepsin I and II
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2003 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 11, no 16, p. 3423-3437Article in journal (Refereed) Published
Abstract [en]

New inhibitors of plasmepsin I and II, the aspartic proteases of the malaria parasite Plasmodium falciparum, are described. From paralell solution phase chemistry, several reversed-statine type isostere inhibitors, many of which are aza-peptides, have been prepared. The synthetic strategy delivers the target compounds in good to high overall yields and with excellent stereochemical control throughout the developed route. The final products were tested for their plasmepsin I and II inhibiting properties and were found to exhibit modest but promising activity. The best inhibitor exhibits Ki values of 250 nM and 1.4 µM for Plm I and II, respectively. © 2003 Elsevier Ltd. All rights reserved.

National Category
Engineering and Technology
Identifiers
urn:nbn:se:liu:diva-46526 (URN)10.1016/S0968-0896(03)00312-2 (DOI)
Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2017-12-13
Dahlgren, A., Kvarnström, I., Vrang, L., Hamelink, E., Hallberg, A., Rosenquist, A. & Samuelsson, B. (2003). Solid-phase library synthesis of reversed-statine type inhibitors of the malarial aspartyl proteases plasmepsin I and II. Bioorganic & Medicinal Chemistry, 11(6), 827-841
Open this publication in new window or tab >>Solid-phase library synthesis of reversed-statine type inhibitors of the malarial aspartyl proteases plasmepsin I and II
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2003 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 11, no 6, p. 827-841Article in journal (Refereed) Published
Abstract [en]

With the aim to develop inhibitors of the plasmepsin I and II aspartic proteases of the malaria parasite Plasmodium falciparum, we have synthesized sets of libraries from novel reversed-statine isosteres, using a combination of solution phase and solid phase chemistry. The synthetic strategy furnishes the library compounds in good to high overall yields and with excellent stereochemical control throughout the developed route. The products were evaluated for their plasmepsin I and II inhibiting properties and were found to exhibit modest but promising activity. The best inhibitor exhibits an in vitro activity of 28% inhibition of plasmepsin II at an inhibitor concentration of 0.5 µM (Ki for Plm II=5.4 µM). © 2003 Elsevier Science Ltd. All rights reserved.

National Category
Engineering and Technology
Identifiers
urn:nbn:se:liu:diva-46636 (URN)10.1016/S0968-0896(02)00568-0 (DOI)
Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2017-12-13
Dahlgren, A., Johansson, P.-O., Kvarnström, I., Musil, D., Nilsson, I. & Samuelsson, B. (2002). Novel morpholinone-based D-Phe-Pro-Arg mimics as potential thrombin inhibitors: design, synthesis, and X-ray crystal structure of an enzyme inhibitor complex. Bioorganic & Medicinal Chemistry, 10(6), 1829-1839
Open this publication in new window or tab >>Novel morpholinone-based D-Phe-Pro-Arg mimics as potential thrombin inhibitors: design, synthesis, and X-ray crystal structure of an enzyme inhibitor complex
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2002 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 10, no 6, p. 1829-1839Article in journal (Refereed) Published
Abstract [en]

A morpholinone structural motif derived from d(+)- and l(−)-malic acid has been used as a mimic of d-Phe-Pro in the thrombin inhibiting tripeptide d-Phe-Pro-Arg. In place of Arg the more rigid P1 truncated p-amidinobenzylamine (Pab) or 2-amino-5-aminomethyl-3-methyl-pyridine have been utilized. The synthetic strategy developed readily delivers these novel thrombin inhibitors used to probe the α-thrombin inhibitor binding site. The best candidate in this series of thrombin inhibitors exhibits an in vitro IC50 of 720 nM. The X-ray crystal structure of this candidate co-crystallized with α-thrombin is discussed.

National Category
Engineering and Technology
Identifiers
urn:nbn:se:liu:diva-47039 (URN)10.1016/S0968-0896(02)00023-8 (DOI)
Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2017-12-13
Dahlgren, A., Branalt, J., Kvarnström, I., Nilsson, I., Musil, D. & Samuelsson, B. (2002). Synthesis of potential thrombin inhibitors. Incorporation of tartaric acid templates as P2 proline mimetics. Bioorganic & Medicinal Chemistry, 10(5), 1567-1580
Open this publication in new window or tab >>Synthesis of potential thrombin inhibitors. Incorporation of tartaric acid templates as P2 proline mimetics
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2002 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 10, no 5, p. 1567-1580Article in journal (Refereed) Published
Abstract [en]

With the objective to prepare novel non-peptidic thrombin inhibitors, bioisosteres of the inhibitory tripeptide D-Phe-Pro-Arg chain have been examined. Thus, the P1 Arg was replaced with p-amidinobenzylamine, an elongated homologue of the same and with 2,5-dichloro benzylamine. The P2-P3, D-Phe-Pro, was replaced with a novel tartaric acid template coupled to a series of readily available, mainly lipophilic, amines. Some of these compounds exhibit promising thrombin inhibition activity in vitro, IC50~5.9 µM. © 2002 Elsevier Science Ltd. All rights reserved.

National Category
Engineering and Technology
Identifiers
urn:nbn:se:liu:diva-47060 (URN)10.1016/S0968-0896(01)00426-6 (DOI)
Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2017-12-13
Sandgren, V., Belda, O., Johansson, P.-O., Kvarnström, I., Dahlgren, A. & Samuelsson, B.Design and synthesis of novel macrocyclic BACE-1 inhibitors.
Open this publication in new window or tab >>Design and synthesis of novel macrocyclic BACE-1 inhibitors
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

A series of arylketo-containing P1-P3 linked macrocyclic inhibitors was designed and synthesized and compared with a previously known and extensively used corresponding P2 isophthalamide moiety with the aim to improve on permeability whilst retaining the enzyme and cell-based potencies. Several inhibitors displayed a substantial increase in Caco-2 cell-based permeability and notably also with retained potencies, showing that this approach might lead to centrally active BACE-1 inhibitors.

National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-76173 (URN)
Available from: 2012-03-29 Created: 2012-03-29 Last updated: 2012-03-29Bibliographically approved
Sandgren, V., Kvarnström, I. & Dahlgren, A.Exploration of the active site of BACE-1: Design and synthesis of inhibitors incorporating substituted cyclopentanes in the P2 position.
Open this publication in new window or tab >>Exploration of the active site of BACE-1: Design and synthesis of inhibitors incorporating substituted cyclopentanes in the P2 position
(English)Manuscript (preprint) (Other academic)
Abstract [en]

A novel hydroxyethylene (HE) core structure with an O-methyl group in the P1´ position, previously reported by our group, has been further evaluated by introducing a substituted cyclopentane moiety in the P2 position. Results from earlier published work suggest that inhibitors containing the novel O-methyl HE core may result in inhibitors displaying promising potency against BACE-1 as well as selectivity towards cathepsin D. Furthermore, there is a general need for new and improved moieties in the P2 position for many BACE-1 inhibitors, e.g., the widely used substituted P2 isophthalamide structure often gives rise to inhibitors suffering from poor pharmacokinetics, including insufficient blood-brain barrier permeability. Different stereoisomers of the P2 cyclopentane moieties and a selection of P3 substituents have been examined. In addition, a macrocyclization study linking the P1 and P3 moieties was performed and biological results are discussed.

National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-76170 (URN)
Available from: 2012-03-29 Created: 2012-03-29 Last updated: 2012-03-29Bibliographically approved
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