uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Design and Synthesis of Hepatitis C Virus NS3 Protease Inhibitors: Targeting Different Genotypes and Drug-Resistant Variants
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Since the first approved hepatitis C virus (HCV) NS3 protease inhibitors in 2011, numerous direct acting antivirals (DAAs) have reached late stages of clinical trials. Today, several combination therapies, based on different DAAs, with or without the need of pegylated interferon-α injection, are available for chronic HCV infections. The chemical foundation of the approved and late-stage HCV NS3 protease inhibitors is markedly similar. This could partly explain the cross-resistance that have emerged under the pressure of NS3 protease inhibitors. The first-generation NS3 protease inhibitors were developed to efficiently inhibit genotype 1 of the virus and were less potent against other genotypes.

The main focus in this thesis was to design and synthesize a new class of 2(1H)-pyrazinone based HCV NS3 protease inhibitors, structurally dissimilar to the inhibitors evaluated in clinical trials or approved, potentially with a unique resistance profile and with a broad genotypic coverage. Successive modifications were performed around the pyrazinone core structure to clarify the structure-activity relationship; a P3 urea capping group was found valuable for inhibitory potency, as were elongated R6 residues possibly directed towards the S2 pocket. Dissimilar to previously developed inhibitors, the P1’ aryl acyl sulfonamide was not essential for inhibition as shown by equally good inhibitory potency for P1’ truncated inhibitors. In vitro pharmacokinetic (PK) evaluations disclosed a marked influence from the R6 moiety on the overall drug-properties and biochemical evaluation of the inhibitors against drug resistant enzyme variants showed retained inhibitory potency as compared to the wild-type enzyme. Initial evaluation against genotype 3a displayed micro-molar potencies. Lead optimization, with respect to improved PK properties, were also performed on an advanced class of HCV NS3 protease inhibitors, containing a P2 quinazoline substituent in combination with a macro-cyclic proline urea scaffold with nano-molar cell based activities.

Moreover, an efficient Pd-catalyzed C-N urea arylation protocol, enabling high yielding introductions of advanced urea substituents to the C3 position of the pyrazinone, and a Pd-catalyzed carbonylation procedure, to obtain acyl sulfinamides, were developed. These methods can be generally applicable in the synthesis of bioactive compounds containing peptidomimetic scaffolds and carboxylic acid bioisosteres.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. , 108 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 197
Keyword [en]
hepatitis C virus, HCV, NS3 protease inhibitors, structure-activity relationship, 2(1H)-pyrazinone, quinazoline, resistance, Pd catalysis
National Category
Organic Chemistry Other Chemistry Topics
Research subject
Medicinal Chemistry; Pharmaceutical Science
Identifiers
URN: urn:nbn:se:uu:diva-243317ISBN: 978-91-554-9166-6 (print)OAI: oai:DiVA.org:uu-243317DiVA: diva2:787019
Public defence
2015-03-27, B41 BMC, Husargatan 3, Uppsala, 09:15 (Swedish)
Opponent
Supervisors
Available from: 2015-03-05 Created: 2015-02-08 Last updated: 2015-03-12Bibliographically approved
List of papers
1. Synthesis and SAR of potent inhibitors of the Hepatitis C virus NS3/4A protease: Exploration of P2 quinazoline substituents
Open this publication in new window or tab >>Synthesis and SAR of potent inhibitors of the Hepatitis C virus NS3/4A protease: Exploration of P2 quinazoline substituents
Show others...
2010 (English)In: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 20, no 14, 4004-4011 p.Article in journal (Refereed) Published
Abstract [en]

Novel NS3/4A protease inhibitors comprising quinazoline derivatives as P2 substituent were synthesized. High potency inhibitors displaying advantageous PK properties have been obtained through the optimization of quinazoline P2 substituents in three series exhibiting macrocyclic P2 cyclopentane dicarboxylic acid and P2 proline urea motifs. For the quinazoline moiety it was found that 8-methyl substitution in the P2 cyclopentane dicarboxylic acid series improved on the metabolic stability in human liver microsomes. By comparison, the proline urea series displayed advantageous Caco-2 permeability over the cyclopentane series. Pharmacokinetic properties in vivo were assessed in rat on selected compounds, where excellent exposure and liver-to-plasma ratios were demonstrated for a member of the 14-membered quinazoline substituted P2 proline urea series. (C) 2010 Elsevier Ltd. All rights reserved.

Keyword
HCV, NS3/4A protease, Inhibitors, P2 substituent, Quinazoline, Replicon assay, In vitro, DMPK, In vivo PK
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-136039 (URN)10.1016/j.bmcl.2010.05.029 (DOI)000279258800001 ()
Available from: 2010-12-09 Created: 2010-12-09 Last updated: 2017-12-11Bibliographically approved
2. Achiral Pyrazinone-Based Inhibitors of the Hepatitis C Virus NS3 Protease and Drug-Resistant Variants with Elongated Substituents Directed Toward the S2 Pocket
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
Show others...
2014 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 57, no 5, 1790-1801 p.Article 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: 2017-12-07Bibliographically approved
3. Discovery of pyrazinone based compounds that potently inhibit the drug resistant enzyme variant R155K of the hepatitis C virus NS3 protease
Open this publication in new window or tab >>Discovery of pyrazinone based compounds that potently inhibit the drug resistant enzyme variant R155K of the hepatitis C virus NS3 protease
Show others...
2016 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 24, no 12, 2603-2620 p.Article in journal (Refereed) Published
Abstract [en]

Herein, we present the design and synthesis of 2(1H)-pyrazinone based HCV NS3 protease inhibitors with variations in the C-terminus. Biochemical evaluation was performed using genotype 1a, both the wildtype and the drug resistant enzyme variant, R155K. Surprisingly, compounds without an acidic sulfonamide retained good inhibition, challenging our previous molecular docking model. Moreover, selected compounds in this series showed nanomolar potency against R155K NS3 protease; which generally confer resistance to all HCV NS3 protease inhibitors approved or in clinical trials. These results further strengthen the potential of this novel substance class, being very different to the approved drugs and clinical candidates, in the development of inhibitors less sensitive to drug resistance.

Keyword
Hepatitis C virus; Drug resistance; Pyrazinone; NS3 protease inhibitors; R155K
National Category
Organic Chemistry
Research subject
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-243315 (URN)10.1016/j.bmc.2016.03.066 (DOI)000376727800002 ()27160057 (PubMedID)
Funder
Swedish Research Council, D0571301
Available from: 2015-02-08 Created: 2015-02-08 Last updated: 2017-12-04Bibliographically approved
4. Efficient and Selective Palladium-Catalysed C-3 Urea Couplings to 3,5-Dichloro-2(1H)-pyrazinones
Open this publication in new window or tab >>Efficient and Selective Palladium-Catalysed C-3 Urea Couplings to 3,5-Dichloro-2(1H)-pyrazinones
Show others...
2015 (English)In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, no 5, 978-986 p.Article 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
5. Palladium-catalyzed carbonylation of aryl iodides with sulfinamides
Open this publication in new window or tab >>Palladium-catalyzed carbonylation of aryl iodides with sulfinamides
(English)Manuscript (preprint) (Other academic)
Keyword
palladium
National Category
Organic Chemistry
Research subject
Medicinal Chemistry; Chemistry with specialization in Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-243257 (URN)
Available from: 2015-02-06 Created: 2015-02-06 Last updated: 2015-03-11

Open Access in DiVA

fulltext(5860 kB)886 downloads
File information
File name FULLTEXT01.pdfFile size 5860 kBChecksum SHA-512
f4aac548970ceea6664891c249ae9611aeeeb0ebff302d0bb472258b0f3e2127b94d9a0fd29f75b8d56ece4d2607f173ba840ad5b89fe8a200894be9147bbfb0
Type fulltextMimetype application/pdf
Buy this publication >>

Authority records BETA

Belfrage, Anna Karin

Search in DiVA

By author/editor
Belfrage, Anna Karin
By organisation
Organic Pharmaceutical Chemistry
Organic ChemistryOther Chemistry Topics

Search outside of DiVA

GoogleGoogle Scholar
Total: 886 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

isbn
urn-nbn

Altmetric score

isbn
urn-nbn
Total: 1185 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf