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Kvarnström, Ingemar
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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
Öppna denna publikation i ny flik eller fönster >>Design and Synthesis of Novel Arylketo-containing P1-P3 Linked Macro-cyclic BACE-1 Inhibitors
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2015 (Engelska)Ingår i: Open Medicinal Chemistry Journal, ISSN 1874-1045, Vol. 9, s. 13-26Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
Bussum, Netherlands: Bentham Open, 2015
Nyckelord
Alzheimer’s disease, BACE-1 inhibition, cellular permeability, macrocycles, ring-closing metathesis, X-ray structure
Nationell ämneskategori
Läkemedelskemi
Identifikatorer
urn:nbn:se:liu:diva-120598 (URN)10.2174/1874104501509010013 (DOI)25937848 (PubMedID)
Tillgänglig från: 2015-08-18 Skapad: 2015-08-18 Senast uppdaterad: 2018-01-11Bibliografiskt granskad
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
Öppna denna publikation i ny flik eller fönster >>Design and synthesis of hydroxyethylene-based BACE-1 inhibitors incorporating extended P1 substituents
2013 (Engelska)Ingår i: Open Medicinal Chemistry Journal, ISSN 1874-1045, Vol. 7, s. 1-15Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
Bussum, Netherlands: Bentham Open, 2013
Nationell ämneskategori
Naturvetenskap
Identifikatorer
urn:nbn:se:liu:diva-76171 (URN)10.2174/1874104501307010001 (DOI)
Tillgänglig från: 2012-03-29 Skapad: 2012-03-29 Senast uppdaterad: 2017-12-07Bibliografiskt granskad
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
Öppna denna publikation i ny flik eller fönster >>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 (Engelska)Ingår i: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 29, nr 14, s. 4377-4389Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
Elsevier, 2012
Nyckelord
Alzheimer’s disease; BACE-1 inhibition; Macrocycles; Hydroxyethylamine (HEA) isostere
Nationell ämneskategori
Naturvetenskap
Identifikatorer
urn:nbn:se:liu:diva-76172 (URN)10.1016/j.bmc.2012.05.039 (DOI)000305952500023 ()
Anmärkning

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

Tillgänglig från: 2012-03-29 Skapad: 2012-03-29 Senast uppdaterad: 2017-12-07Bibliografiskt granskad
Wångsell, F., Gustafsson, K., Kvarnström, I., Borkakoti, N., Edlund, M., Jansson, K., . . . Samuelsson, B. (2010). Synthesis of potent BACE-1 inhibitors incorporating a hydroxyethylene isostere as central core. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 45(3), 870-882
Öppna denna publikation i ny flik eller fönster >>Synthesis of potent BACE-1 inhibitors incorporating a hydroxyethylene isostere as central core
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2010 (Engelska)Ingår i: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, ISSN 0223-5234, Vol. 45, nr 3, s. 870-882Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

We herein describe the design and synthesis of a series of BACE-1 inhibitors incorporating a P1-substituted hydroxyl ethylene transition state isostere. The synthetic route starting from commercially available carbohydrates yielded a pivotal lactone intermediate with excellent stereochemical control which subsequently could be diversified at the PI-position. The final inhibitors were optimized using three different amines to provide the residues in the P2-P3 position and three different acids affording the residues in the P2-P3 position. In addition we report on the stereochemical preference of the P1-methyl substituent in the synthesized inhibitors. All inhibitors were evaluated in an in vitro BACE-I assay where the most potent inhibitor, 34-(R), exhibited a BACE-1 IC50 Value of 3.1 nM.

Nyckelord
Alzheimers disease, BACE-1 inhibitors, Hydroxylethylene, Transition state isostere
Nationell ämneskategori
Teknik och teknologier
Identifikatorer
urn:nbn:se:liu:diva-54612 (URN)10.1016/j.ejmech.2009.11.013 (DOI)000275404900003 ()
Tillgänglig från: 2010-03-26 Skapad: 2010-03-26 Senast uppdaterad: 2010-03-26
Bäck, M., Nyhlén, J., Kvarnström, I., Appelgren, S., Borkakoti, N., Jansson, K., . . . Samuelsson, B. (2008). Design, synthesis and SAR of potent statine-based BACE-1 inhibitors: exploration of P1 phenoxy and benzyloxy residues.. Bioorganic & medicinal chemistry, 16(21), 9471-9486
Öppna denna publikation i ny flik eller fönster >>Design, synthesis and SAR of potent statine-based BACE-1 inhibitors: exploration of P1 phenoxy and benzyloxy residues.
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2008 (Engelska)Ingår i: Bioorganic & medicinal chemistry, ISSN 1464-3391, Vol. 16, nr 21, s. 9471-9486Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Several BACE-1 inhibitors with low nanomolar level activities, encompassing a statine-based core structure with phenyloxymethyl- and benzyloxymethyl residues in the P1 position, are presented. The novel P1 modification introduced to allow the facile exploration of the S1 binding pocket of BACE-1, delivered highly promising inhibitors.

Nyckelord
Alzheimer’s disease, BACE-1 inhibitors, P1 modifications, Peptidomimetics
Nationell ämneskategori
Naturvetenskap
Identifikatorer
urn:nbn:se:liu:diva-17848 (URN)10.1016/j.bmc.2008.09.041 (DOI)18842420 (PubMedID)
Tillgänglig från: 2009-04-22 Skapad: 2009-04-22 Senast uppdaterad: 2009-04-22Bibliografiskt granskad
Bäck, M., Johansson, P.-O., Wångsell, F., Thorstensson, F., Kvarnström, I., Ayesa, S., . . . Samuelsson, B. (2007). Novel potent macrocyclic inhibitors of the hepatitis C virus NS3 protease: use of cyclopentane and cyclopentene P2-motifs.. Bioorganic & Medicinal Chemistry, 15(22), 7184-7202
Öppna denna publikation i ny flik eller fönster >>Novel potent macrocyclic inhibitors of the hepatitis C virus NS3 protease: use of cyclopentane and cyclopentene P2-motifs.
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2007 (Engelska)Ingår i: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 15, nr 22, s. 7184-7202Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Several highly potent novel HCV NS3 protease inhibitors have been developed from two inhibitor series containing either a P2 trisubstituted macrocyclic cyclopentane- or a P2 cyclopentene dicarboxylic acid moiety as surrogates for the widely used N-acyl-(4R)-hydroxyproline in the P2 position. These inhibitors were optimized for anti HCV activities through examination of different ring sizes in the macrocyclic systems and further by exploring the effect of P4 substituent removal on potency. The target molecules were synthesized from readily available starting materials, furnishing the inhibitor compounds in good overall yields. It was found that the 14-membered ring system was the most potent in these two series and that the corresponding 13-, 15-, and 16-membered macrocyclic rings delivered less potent inhibitors. Moreover, the corresponding P1 acylsulfonamides had superior potencies over the corresponding P1 carboxylic acids. It is noteworthy that it has been possible to develop highly potent HCV protease inhibitors that altogether lack the P4 substituent. Thus the most potent inhibitor described in this work, inhibitor 20, displays a K(i) value of 0.41 nM and an EC(50) value of 9 nM in the subgenomic HCV replicon cell model on genotype 1b. To the best of our knowledge this is the first example described in the literature of a HCV protease inhibitor displaying high potency in the replicon assay and lacking the P4 substituent, a finding which should facilitate the development of orally active small molecule inhibitors against the HCV protease.

Nationell ämneskategori
Naturvetenskap
Identifikatorer
urn:nbn:se:liu:diva-17846 (URN)10.1016/j.bmc.2007.07.027 (DOI)17845856 (PubMedID)
Tillgänglig från: 2009-04-22 Skapad: 2009-04-22 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
Thorstensson, F., Wångsell, F., Kvarnström, I., Vrang, L., Hamelink, E., Hallberg, A., . . . Samuelsson, B. (2007). Synthesis of Novel Potent Hepatitis C Virus NS3 Protease Inhibitors: Discovery of 4-Hydroxy-cyclopent-2-ene-1,2-dicarboxylic Acid as a N-Acyl-L-Hydroxyproline Bioisostere. Bioorganic & medicinal chemistry, 15(2), 827-838
Öppna denna publikation i ny flik eller fönster >>Synthesis of Novel Potent Hepatitis C Virus NS3 Protease Inhibitors: Discovery of 4-Hydroxy-cyclopent-2-ene-1,2-dicarboxylic Acid as a N-Acyl-L-Hydroxyproline Bioisostere
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2007 (Engelska)Ingår i: Bioorganic & medicinal chemistry, ISSN 0968-0896, Vol. 15, nr 2, s. 827-838Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Potent tetrapeptidic inhibitors of the HCV NS3 protease have been developed incorporating 4-hydroxy-cyclopent-2-ene-1,2-dicarboxylic acid as a new N-acyl-l-hydroxyproline mimic. The hydroxycyclopentene template was synthesized in eight steps from commercially available (syn)-tetrahydrophthalic anhydride. Three different amino acids were explored in the P1-position and in the P2-position the hydroxyl group of the cyclopentene template was substituted with 7-methoxy-2-phenyl-quinolin-4-ol. The P3/P4-positions were then optimized from a set of six amino acid derivatives. All inhibitors were evaluated in an in vitro assay using the full-length NS3 protease. Several potent inhibitors were identified, the most promising exhibiting a Ki value of 1.1 nM.

Nyckelord
HCV; NS3; Protease inhibitor; N-Acyl-l-hydroxyproline mimic; 4-Hydroxy-cyclopent-2-ene-1, 2-dicarboxylic acid; Cyclopentene
Nationell ämneskategori
Naturvetenskap
Identifikatorer
urn:nbn:se:liu:diva-13983 (URN)10.1016/j.bmc.2006.10.044 (DOI)
Tillgänglig från: 2006-09-14 Skapad: 2006-09-14 Senast uppdaterad: 2009-05-15
Johansson, P.-O., Bäck, M., Kvarnström, I., Jansson, K., Vrang, L., Hamelink, E., . . . Samuelsson, B. (2006). Potent inhibitors of the hepatitis C virus NS3 protease: use of a novel P2 cyclopentane-derived template. Bioorganic & Medicinal Chemistry, 14(15), 5136-5151
Öppna denna publikation i ny flik eller fönster >>Potent inhibitors of the hepatitis C virus NS3 protease: use of a novel P2 cyclopentane-derived template
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2006 (Engelska)Ingår i: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 14, nr 15, s. 5136-5151Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The HCV NS3 protease is essential for replication of the hepatitis C virus (HCV) and therefore constitutes a promising new drug target for anti-HCV therapy. Several potent and promising HCV NS3 protease inhibitors, some of which display low nanomolar activities, were identified from a series of novel inhibitors incorporating a trisubstituted cyclopentane dicarboxylic acid moiety as a surrogate for the widely used N-acyl-(4R)-hydroxyproline in the P2 position.

Nyckelord
HCV, NS3, Protease inhibitor, Cyclopentane-derived P2 scaffold
Nationell ämneskategori
Naturvetenskap
Identifikatorer
urn:nbn:se:liu:diva-14308 (URN)10.1016/j.bmc.2006.04.008 (DOI)
Tillgänglig från: 2007-02-21 Skapad: 2007-02-21 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
Johansson, P.-O., Lindberg, J., Blackman, M. J., Kvarnström, I., Vrang, L., Hamelink, E., . . . Samuelsson, B. (2005). Design and synthesis of potent inhibitors of plasmepsin I and II: x-ray crystal structure of inhibitor in complex with plasmepsin II. Journal of Medicinal Chemistry, 48(13), 4400-4409
Öppna denna publikation i ny flik eller fönster >>Design and synthesis of potent inhibitors of plasmepsin I and II: x-ray crystal structure of inhibitor in complex with plasmepsin II
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2005 (Engelska)Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 48, nr 13, s. 4400-4409Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

New and potent inhibitors of the malarial aspartic proteases plasmepsin (Plm) I and II, from the deadliest malaria parasite Plasmodium falciparum, have been synthesized utilizing Suzuki coupling reactions on previously synthesized bromobenzyloxy-substituted statine-like inhibitors. The enzyme inhibition activity has been improved up to eight times by identifying P1 substituents that effectively bind to the continuous S1-S3 crevice of Plasmepsin I and II. By replacement of the bromo atom in the P1 p-bromobenzyloxy-substituted inhibitors with different aryl substituents, several inhibitors exhibiting Ki values in the low nanomolar range for both Plm I and II have been identified. Some of these inhibitors are also effective in attenuating parasite growth in red blood cells, with the best inhibitors, compounds 2 and 4, displaying 70% and 83% inhibition, respectively, at a concentration of 5 μM. The design was partially guided by the X-ray crystal structure disclosed herein of the previously synthesized inhibitor 1 in complex with plasmepsin II. © 2005 American Chemical Society.

Nationell ämneskategori
Teknik och teknologier
Identifikatorer
urn:nbn:se:liu:diva-50477 (URN)10.1021/jm040884n (DOI)
Tillgänglig från: 2009-10-11 Skapad: 2009-10-11 Senast uppdaterad: 2017-12-12
Johansson, P.-O., Chen, Y., Belfrage, A. K., Blackman, M. J., Kvarnström, I., Jansson, K., . . . Samuelsson, B. (2004). Design and Synthesis of Potent Inhibitors of the Malaria Aspartyl Proteases. Journal of Medicinal Chemistry, 47, 3353-3366
Öppna denna publikation i ny flik eller fönster >>Design and Synthesis of Potent Inhibitors of the Malaria Aspartyl Proteases
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2004 (Engelska)Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 47, s. 3353-3366Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

  

Ort, förlag, år, upplaga, sidor
American Chemical Society (ACS), 2004
Nationell ämneskategori
Naturvetenskap
Identifikatorer
urn:nbn:se:liu:diva-39265 (URN)10.1021/jm031106i (DOI)47693 (Lokalt ID)47693 (Arkivnummer)47693 (OAI)
Tillgänglig från: 2009-10-10 Skapad: 2009-10-10 Senast uppdaterad: 2018-05-25
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