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Achiral Pyrazinone-Based Inhibitors of the Hepatitis C Virus NS3 Protease and Drug-Resistant Variants with Elongated Substituents Directed Toward the S2 Pocket
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
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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.

Place, publisher, year, edition, pages
2014. Vol. 57, no 5, 1790-1801 p.
National Category
Medicinal Chemistry
Research subject
Chemistry with specialization in Organic Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-172003DOI: 10.1021/jm301887fISI: 000333005800011OAI: oai:DiVA.org:uu-172003DiVA: diva2:513239
Available from: 2012-03-31 Created: 2012-03-31 Last updated: 2017-12-07Bibliographically approved
In thesis
1. Design and Synthesis of Enzyme Inhibitors Against Infectious Diseases: Targeting Hepatitis C Virus NS3 Protease and Mycobacterium tuberculosis Ribonucleotide Reductase
Open this publication in new window or tab >>Design and Synthesis of Enzyme Inhibitors Against Infectious Diseases: Targeting Hepatitis C Virus NS3 Protease and Mycobacterium tuberculosis Ribonucleotide Reductase
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Infectious diseases, including hepatitis C and tuberculosis, claim the lives of over 15 million people each year. Hepatitis C is caused by the hepatitis C virus (HCV) which infects the liver and can ultimately result in liver transplantation. HCV is very adaptive as a result of its high mutation rate. Thus, there is a potential high risk for the development of drug resistance and also a possible cross-resistance due to a structural similarity between many of the HCV NS3 protease inhibitors currently in clinical trial and on the market, that all are based on a P2-proline or a proline mimic. Thus, part of the research behind this thesis was to explore a new structural P3-P2 unit for the NS3 protease inhibitors, a 2(1H)-pyrazinone moiety. A microwave-assisted protocol was developed, and the 2(1H)-pyrazinone core was synthesized in only 2 × 10 min. A series of optimization steps resulted in several submicromolar 2(1H)-pyrazinone-containing NS3 protease inhibitors that performed well against drug-resistant NS3 protease variants. The key modifications were: exchanging the unstable carbamate P3 capping group for a stable urea functionality, transferring the P2 group from the amino acid residue to the pyrazinone ring and elongating the substituent, and using an aromatic acyl sulfonamide in the P1-P1' position.

The causative agent of tuberculosis is Mycobacterium tuberculosis (Mtb), which currently infects one third of the world's population. No new TB drugs have been approved in nearly 50 years and drug resistance has been observed for all of the current first-line drugs. Because of the importance of identifying novel drug targets, the ribonucleotide reductase (RNR) enzyme was investigated. The RNR enzyme consists of two R1 and two R2 subunits and is essential for Mtb replication. Starting from hits identified in a virtual screening program, a small library of low molecular weight inhibitors of the association between the R1 and R2 subunits was designed and synthesized. The compounds with the strongest affinity for the R1 subunit of RNR were further evaluated in an orthogonal activity assay. Two RNR inhibitors with promising antimycobacterial effects were identified, which can serve as leads in the further optimization of this class of compounds.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 85 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 160
National Category
Medicinal Chemistry
Research subject
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-172341 (URN)978-91-554-8345-6 (ISBN)
Public defence
2012-05-25, BMC, B42, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2012-05-03 Created: 2012-04-04 Last updated: 2012-08-01Bibliographically approved
2. Design and Synthesis of Hepatitis C Virus NS3 Protease Inhibitors: Targeting Different Genotypes and Drug-Resistant Variants
Open this publication in new window or tab >>Design and Synthesis of Hepatitis C Virus NS3 Protease Inhibitors: Targeting Different Genotypes and Drug-Resistant Variants
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
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:nbn:se:uu:diva-243317 (URN)978-91-554-9166-6 (ISBN)
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

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Publisher's full texthttp://pubs.acs.org/doi/abs/10.1021/jm301887f

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Gising, JohanBelfrage, Anna KarinAlogheli, HibaEhrenberg, AngelicaÅkerblom, EvaSvensson, RichardArtursson, PerAnders, KarlénDanielsson, U. HelenaLarhed, MatsSandström, Anja

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Gising, JohanBelfrage, Anna KarinAlogheli, HibaEhrenberg, AngelicaÅkerblom, EvaSvensson, RichardArtursson, PerAnders, KarlénDanielsson, U. HelenaLarhed, MatsSandström, Anja
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Organic Pharmaceutical ChemistryDepartment of Chemistry - BMCDepartment of Pharmacy
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