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Åkerblom, Eva
Publications (10 of 16) Show all publications
Belfrage, A. K., Abdurakhmanov, E., Åkerblom, E., Brandt, P., Alogheli, H., Neyts, J., . . . Johansson, A. (2018). Pan-NS3 protease inhibitors of hepatitis C virus based on an R3-elongated pyrazinone scaffold. European Journal of Medicinal Chemistry, 148, 453-464
Open this publication in new window or tab >>Pan-NS3 protease inhibitors of hepatitis C virus based on an R3-elongated pyrazinone scaffold
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2018 (English)In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 148, p. 453-464Article in journal (Refereed) Published
Abstract [en]

Herein, we present the design and synthesis of 2(1H)-pyrazinone based HCV NS3 protease inhibitors and show that elongated R-3 urea substituents were associated with increased inhibitory potencies over several NS3 protein variants. The inhibitors are believed to rely on beta-sheet mimicking hydrogen bonds which are similar over different genotypes and current drug resistant variants and correspond to the beta-sheet interactions of the natural peptide substrate. Inhibitor 36, for example, with a urea substituent including a cyclic imide showed balanced nanomolar inhibitory potencies against genotype la, both wild-type (K-i=30 nM) and R155K (K-i=2 nM), and genotype 3a (K-i=5 nM).

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
Hepatitis C, NS3, Genotype 3, Resistance, Pyrazinone
National Category
Medicinal Chemistry
Research subject
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-340862 (URN)10.1016/j.ejmech.2018.02.032 (DOI)000428824700036 ()
Funder
Swedish Research Council, D0571301
Available from: 2018-02-04 Created: 2018-02-04 Last updated: 2018-05-31Bibliographically approved
Belfrage, A. K., Gising, J., Svensson, F., Åkerblom, E., Sköld, C. & Sandström, A. (2015). Efficient and Selective Palladium-Catalysed C-3 Urea Couplings to 3,5-Dichloro-2(1H)-pyrazinones. European Journal of Organic Chemistry (5), 978-986
Open this publication in new window or tab >>Efficient and Selective Palladium-Catalysed C-3 Urea Couplings to 3,5-Dichloro-2(1H)-pyrazinones
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2015 (English)In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, no 5, p. 978-986Article in journal (Refereed) Published
Abstract [en]

The development of a robust palladium-catalysed urea N-arylation protocol to install various ureas at the 3-position of the 2(1H)-pyrazinone scaffold is described. The method involves Pd(OAc)2 in combination with bidentate ligands, xantphos [4,5-bis(diphenylphosphino)-9,9-dimethylxanthene] in particular, and resulted in good to excellent coupling yields of aliphatic, aromatic, and sterically hindered ureas. Furthermore, the C-3 chlorine was shown to be selectively displaced in the presence of aryl halide ureas, and this finding was supported by density functional theory (DFT) calculations. This allows further diversification of the scaffold for the production of compound libraries. Overall, the protocol facilitates further exploitation of pyrazinones as beta-sheet-inducing scaffolds in the development of sophisticated peptidomimetics/protease inhibitors. This is exemplified here by the synthesis of a new pyrazinone-based hepatitis C virus (HCV) NS3 protease inhibitor.

National Category
Organic Chemistry
Research subject
Chemistry with specialization in Organic Chemistry; Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-243254 (URN)10.1002/ejoc.201403405 (DOI)000349391700009 ()
Available from: 2015-02-06 Created: 2015-02-06 Last updated: 2017-12-04Bibliographically approved
Gising, J., Belfrage, A. K., Alogheli, H., Ehrenberg, A., Åkerblom, E., Svensson, R., . . . Sandström, A. (2014). Achiral Pyrazinone-Based Inhibitors of the Hepatitis C Virus NS3 Protease and Drug-Resistant Variants with Elongated Substituents Directed Toward the S2 Pocket. Journal of Medicinal Chemistry, 57(5), 1790-1801
Open this publication in new window or tab >>Achiral Pyrazinone-Based Inhibitors of the Hepatitis C Virus NS3 Protease and Drug-Resistant Variants with Elongated Substituents Directed Toward the S2 Pocket
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2014 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 57, no 5, p. 1790-1801Article in journal (Refereed) Published
Abstract [en]

Herein we describe the design, synthesis, inhibitory potency, and pharmacokinetic properties of a novel class of achiral peptidomimetic HCV NS3 protease inhibitors. The compounds are based on a dipeptidomimetic pyrazinone glycine P3P2 building block in combination with an aromatic acyl sulfonamide in the P1P1′ position. Structure–activity relationship data and molecular modeling support occupancy of the S2 pocket from elongated R6 substituents on the 2(1H)-pyrazinone core and several inhibitors with improved inhibitory potency down to Ki = 0.11 μM were identified. A major goal with the design was to produce inhibitors structurally dissimilar to the di- and tripeptide-based HCV protease inhibitors in advanced stages of development for which cross-resistance might be an issue. Therefore, the retained and improved inhibitory potency against the drug-resistant variants A156T, D168V, and R155K further strengthen the potential of this class of inhibitors. A number of the inhibitors were tested in in vitro preclinical profiling assays to evaluate their apparent pharmacokinetic properties. The various R6 substituents were found to have a major influence on solubility, metabolic stability, and cell permeability.

National Category
Medicinal Chemistry
Research subject
Chemistry with specialization in Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-172003 (URN)10.1021/jm301887f (DOI)000333005800011 ()
Available from: 2012-03-31 Created: 2012-03-31 Last updated: 2018-01-12Bibliographically approved
Lampa, A., Bergman, S., Svahn Gustafsson, S., Alogheli, H., Åkerblom, E., Lindeberg, G., . . . Sandström, A. (2014). Novel Peptidomimetic Hepatitis C Virus NS3/4A Protease Inhibitors Spanning the P2–P1′ Region [Letter to the editor]. ACS Medicinal Chemistry Letters, 5(3), 249-254
Open this publication in new window or tab >>Novel Peptidomimetic Hepatitis C Virus NS3/4A Protease Inhibitors Spanning the P2–P1′ Region
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2014 (English)In: ACS Medicinal Chemistry Letters, ISSN 1948-5875, E-ISSN 1948-5875, Vol. 5, no 3, p. 249-254Article in journal, Letter (Refereed) Published
Abstract [en]

Herein, novel hepatitis C virus NS3/4A protease inhibitors based on a P2 pyrimidinyloxyphenylglycine in combination with various regioisomers of an aryl acyl sulfonamide functionality in P1 are presented. The P1′ 4-(trifluoromethyl)phenyl side chain was shown to be particularly beneficial in terms of inhibitory potency. Several inhibitors with Ki-values in the nanomolar range were developed and included identification of promising P3-truncated inhibitors spanning from P2–P1′. Of several different P2 capping groups that were evaluated, a preference for the sterically congested Boc group was revealed. The inhibitors were found to retain inhibitory potencies for A156T, D168V, and R155K variants of the protease. Furthermore, in vitro pharmacokinetic profiling showed several beneficial effects on metabolic stability as well as on apparent intestinal permeability from both P3 truncation and the use of the P1′ 4-(trifluoromethyl)phenyl side chain.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-221229 (URN)10.1021/ml400217r (DOI)000333006200005 ()
Available from: 2014-03-26 Created: 2014-03-26 Last updated: 2018-02-04Bibliographically approved
Lampa, A., Alogheli, H., Ehrenberg, A. E., Åkerblom, E., Svensson, R., Artursson, P., . . . Sandström, A. (2014). Vinylated linear P2 pyrimidinyloxyphenylglycine based inhibitors of the HCV NS3/4A protease and corresponding macrocycles. Bioorganic & Medicinal Chemistry, 22(23), 6595-6615
Open this publication in new window or tab >>Vinylated linear P2 pyrimidinyloxyphenylglycine based inhibitors of the HCV NS3/4A protease and corresponding macrocycles
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2014 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 22, no 23, p. 6595-6615Article in journal (Refereed) Published
Abstract [en]

With three recent market approvals and several inhibitors in advanced stages of development, the hepatitis C virus (HCV) NS3/4A protease represents a successful target for antiviral therapy against hepatitis C. As a consequence of dealing with viral diseases in general, there are concerns related to the emergence of drug resistant strains which calls for development of inhibitors with an alternative binding-mode than the existing highly optimized ones. We have previously reported on the use of phenylglycine as an alternative P2 residue in HCV NS3/4A protease inhibitors. Herein, we present the synthesis, structure-activity relationships and in vitro pharmacokinetic characterization of a diverse series of linear and macrocyclic P2 pyrimidinyloxyphenylglycine based inhibitors. With access to vinyl substituents in P3, P2 and P1' positions an initial probing of macrocyclization between different positions, using ring-closing metathesis (RCM) could be performed, after addressing some synthetic challenges. Biochemical results from the wild type enzyme and drug resistant variants (e.g., R155 K) indicate that P3-P1' macrocyclization, leaving the P2 substituent in a flexible mode, is a promising approach. Additionally, the study demonstrates that phenylglycine based inhibitors benefit from p-phenylpyrimidinyloxy and m-vinyl groups as well as from the combination with an aromatic P1 motif with alkenylic P1' elongations. In fact, linear P2-P1' spanning intermediate compounds based on these fragments were found to display promising inhibitory potencies and drug like properties.

Keywords
HCV, NS3, Protease inhibitors, Macrocyclization, Phenylglycine, Metathesis
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-239738 (URN)10.1016/j.bmc.2014.10.010 (DOI)000345287300007 ()
Available from: 2014-12-31 Created: 2014-12-30 Last updated: 2018-02-04Bibliographically approved
Lampa, A., Ehrenberg, A. E., Vema, A., Åkerblom, E., Lindeberg, G., Danielson, U. H., . . . Sandström, A. (2011). P2-P1 ' macrocyclization of P2 phenylglycine based HCV NS3 protease inhibitors using ring-closing metathesis. Bioorganic & Medicinal Chemistry, 19(16), 4917-4927
Open this publication in new window or tab >>P2-P1 ' macrocyclization of P2 phenylglycine based HCV NS3 protease inhibitors using ring-closing metathesis
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2011 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 19, no 16, p. 4917-4927Article in journal (Refereed) Published
Abstract [en]

Macrocyclization is a commonly used strategy to preorganize HCV NS3 protease inhibitors in their bioactive conformation. Moreover, macrocyclization generally leads to greater stability and improved pharmacokinetic properties. In HCV NS3 protease inhibitors, it has been shown to be beneficial to include a vinylated phenylglycine in the P2 position in combination with alkenylic P1' substituents. A series of 14-, 15- and 16-membered macrocyclic HCV NS3 protease inhibitors with the linker connecting the P2 phenylglycine and the alkenylic P1' were synthesized by ring-closing metathesis, using both microwave and conventional heating. Besides formation of the expected macrocycles in cis and trans configuration as major products, both ring-contracted and double-bond migrated isomers were obtained, in particular during formation of the smaller rings (14- and 15-membered rings). All inhibitors had K(i)-values in the nanomolar range, but only one inhibitor type was improved by rigidification. The loss in inhibitory effect can be attributed to a disruption of the beneficial pi-pi interaction between the P2 fragment and H57, which proved to be especially deleterious for the D-phenylglycine epimers.

Keywords
HCV, Protease inhibitors, Macrocyclization, Phenylglycine, Metathesis
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-157240 (URN)10.1016/j.bmc.2011.06.064 (DOI)000293503000025 ()
Available from: 2011-08-31 Created: 2011-08-22 Last updated: 2018-01-12Bibliographically approved
Örtqvist, P., Vema, A., Ehrenberg, A. E., Dahl, G., Rönn, R., Åkerblom, E., . . . Sandström, A. (2010). Structure-activity relationships of HCV NS3 protease inhibitors evaluated on the drug-resistant variants A156T and D168V. Antiviral Therapy, 15(6), 841-852
Open this publication in new window or tab >>Structure-activity relationships of HCV NS3 protease inhibitors evaluated on the drug-resistant variants A156T and D168V
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2010 (English)In: Antiviral Therapy, ISSN 1359-6535, E-ISSN 2040-2058, Vol. 15, no 6, p. 841-852Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: HCV infections are a serious threat to public health. An important drug target is the NS3 protease, for which several inhibitors are in clinical trials. Because of the high mutation rate of the virus, resistance against any HCV-specific drug is likely to become a substantial problem. Structure-activity data for the major resistant variants are therefore needed to guide future designs of protease inhibitors. METHODS: The inhibitory potency of tripeptide NS3 protease inhibitors, with either a P2 proline or phenylglycine, in combination with different P3 and P1-P1' groups, was assessed in enzyme activity assays using the full-length NS3 protein with known resistance-conferring substitutions A156T or D168V. The results obtained from these variants were compared with the inhibition of the wild-type enzyme. Molecular modelling was used to rationalize the biochemical results. RESULTS: Inhibitors combining the P2 proline and P1 (1R,2S)-1-amino-2-vinylcyclopropyl-carboxylic acid (vinylACCA) lost much of their potency on the resistant variants. Exchange of the P2 proline for phenylglycine yielded inhibitors that were equipotent on the wild-type and on the A156T and D168V variants. The same result was obtained from the combination of either the P2 residue with a norvaline or an aromatic scaffold in the P1 position. CONCLUSIONS: The combination of a substituted P2 proline and P1 vinylACCA appears to be the main problem behind the observed resistance. Molecular modelling suggests an enforced change in binding conformation for the P2 proline-based inhibitors, whereas the phenylglycine-based inhibitors retained their wild-type binding conformation in the substituted forms of the enzyme.

National Category
Pharmaceutical Sciences Chemical Sciences
Identifiers
urn:nbn:se:uu:diva-131962 (URN)10.3851/IMP1655 (DOI)000282390300004 ()20834096 (PubMedID)
Available from: 2010-10-12 Created: 2010-10-12 Last updated: 2018-01-12Bibliographically approved
Rönn, R., Lampa, A., Peterson, S. D., Gossas, T., Åkerblom, E., Danielson, U. H., . . . Sandström, A. (2008). Hepatitis C Virus NS3 Protease Inhibitors Comprising a Novel Aromatic P1 Moiety. Bioorganic & Medicinal Chemistry, 16(6), 2955-2967
Open this publication in new window or tab >>Hepatitis C Virus NS3 Protease Inhibitors Comprising a Novel Aromatic P1 Moiety
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2008 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 16, no 6, p. 2955-2967Article in journal (Refereed) Published
Abstract [en]

Inhibition of the hepatitis C virus (HCV) NS3 protease has emerged as an attractive approach to defeat the global hepatitis C epidemic. In this work, we present the synthesis and biochemical evaluation of HCV NS3 protease inhibitors comprising a non-natural aromatic P-1 moiety. A series of inhibitors with aminobenzoyl sulfonamides displaying submicromolar potencies in the full-length NS3 protease assay was prepared through a microwave-irradiated, palladium-catalyzed, amidocarbonylation protocol.

Keywords
HCV, NS3, protease inhibitor, carbonylation, acyl sulfonamide, palladium
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-95748 (URN)10.1016/j.bmc.2007.12.041 (DOI)000255127700023 ()18194867 (PubMedID)
Available from: 2007-04-13 Created: 2007-04-13 Last updated: 2018-01-13Bibliographically approved
Dahl, G., Sandström, A., Åkerblom, E. & Danielson, U. H. (2007). Effects on protease inhibition by modifying of helicase residues in hepatitis C virus nonstructural protein 3. The FEBS Journal, 274(22), 5979-5986
Open this publication in new window or tab >>Effects on protease inhibition by modifying of helicase residues in hepatitis C virus nonstructural protein 3
2007 (English)In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 274, no 22, p. 5979-5986Article in journal (Refereed) Published
Abstract [en]

This study of the full-length bifunctional nonstructural protein 3 from hepatitis C virus (HCV) has revealed that residues in the helicase domain affect the inhibition of the protease. Two residues (Q526 and H528), apparently located in the interface between the S2 and S4 binding pockets of the substrate binding site of the protease, were selected for modification, and three enzyme variants (Q526A, H528A and H528S) were expressed, purified and characterized. The substitutions resulted in indistinguishable Km values and slightly lower kcat values compared to the wild-type. The Ki values for a series of structurally diverse protease inhibitors were affected by the substitutions, with increases or decreases up to 10-fold. The inhibition profiles for H528A and H528S were different, confirming that not only did the removal of the imidazole side chain have an effect, but also that minor differences in the nature of the introduced side chain influenced the characteristics of the enzyme. These results indicate that residues in the helicase domain of nonstructural protein 3 can influence the protease, supporting our hypothesis that full-length hepatitis C virus nonstructural protein 3 should be used for protease inhibitor optimization and characterization. Furthermore, the data suggest that inhibitors can be designed to interact with residues in the helicase domain, potentially leading to more potent and selective compounds.

Keywords
full length, hepatitis C virus, inhibition, nonstructural protein 3, protease
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-17092 (URN)10.1111/j.1742-4658.2007.06120.x (DOI)000250586500020 ()17949436 (PubMedID)
Available from: 2008-06-16 Created: 2008-06-16 Last updated: 2018-01-12Bibliographically approved
Rönn, R., Gossas, T., Sabnis, Y. A., Daoud, H., Åkerblom, E., Danielson, U. H. & Sandström, A. (2007). Evaluation of a diverse set of potential P1 carboxylic acid bioisosteres in hepatitis C virus NS3 protease inhibitors. Bioorganic & Medicinal Chemistry, 15(12), 4057-4068
Open this publication in new window or tab >>Evaluation of a diverse set of potential P1 carboxylic acid bioisosteres in hepatitis C virus NS3 protease inhibitors
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2007 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 15, no 12, p. 4057-4068Article in journal (Refereed) Published
Abstract [en]

There is an urgent need for more efficient therapies for people infected with hepatitis C virus (HCV). HCV NS3 protease inhibitors have shown proof-of-concept in clinical trials, which make the virally encoded NS3 protease an attractive drug target. Product-based NS3 protease inhibitors comprising a P1 C-terminal carboxylic acid have shown to be effective and we were interested in finding alternatives to this crucial carboxylic acid group. Thus, a series of diverse P1 functional groups with different acidity and with possibilities to form a similar, or an even more powerful, hydrogen bond network as compared to the carboxylic acid were synthesized and incorporated into potential inhibitors of the NS3 protease. Biochemical evaluation of the inhibitors was performed in both enzyme and cell-based assays. Several non-acidic C-terminal groups, such as amides and hydrazides, were evaluated but failed to produce inhibitors more potent than the corresponding carboxylic acid inhibitor. The tetrazole moiety, although of similar acidity to a carboxylic acid, provided an inhibitor with mediocre potencies in both assays. However, the acyl cyanamide and the acyl sulfinamide groups rendered compounds with low nanomolar inhibitory potencies and were more potent than the corresponding carboxylic acid inhibitor in the enzymatic assay. Additionally, results from a pH-study suggest that the P1 C-terminal of the inhibitors comprising a carboxylic acid, an acyl sulfonamide or an acyl cyanamide group binds in a similar mode in the active site of the NS3 protease.

Keywords
Bioisostere, HCV, Hepatitis C, NS3, Protease inhibitor
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-17091 (URN)10.1016/j.bmc.2007.03.089 (DOI)000246870400010 ()17449253 (PubMedID)
Available from: 2008-06-16 Created: 2008-06-16 Last updated: 2018-01-12Bibliographically approved
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