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Design and Synthesis of Hepatitis C Virus NS3 Protease Inhibitors: Targeting Different Genotypes and Drug-Resistant Variants
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
2015 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2015. , s. 108
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 197
Nyckelord [en]
hepatitis C virus, HCV, NS3 protease inhibitors, structure-activity relationship, 2(1H)-pyrazinone, quinazoline, resistance, Pd catalysis
Nationell ämneskategori
Organisk kemi Annan kemi
Forskningsämne
Läkemedelskemi; Farmaceutisk vetenskap
Identifikatorer
URN: urn:nbn:se:uu:diva-243317ISBN: 978-91-554-9166-6 (tryckt)OAI: oai:DiVA.org:uu-243317DiVA, id: diva2:787019
Disputation
2015-03-27, B41 BMC, Husargatan 3, Uppsala, 09:15 (Svenska)
Opponent
Handledare
Tillgänglig från: 2015-03-05 Skapad: 2015-02-08 Senast uppdaterad: 2015-03-12Bibliografiskt granskad
Delarbeten
1. Synthesis and SAR of potent inhibitors of the Hepatitis C virus NS3/4A protease: Exploration of P2 quinazoline substituents
Öppna denna publikation i ny flik eller fönster >>Synthesis and SAR of potent inhibitors of the Hepatitis C virus NS3/4A protease: Exploration of P2 quinazoline substituents
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2010 (Engelska)Ingår i: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 20, nr 14, s. 4004-4011Artikel i tidskrift (Refereegranskat) 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.

Nyckelord
HCV, NS3/4A protease, Inhibitors, P2 substituent, Quinazoline, Replicon assay, In vitro, DMPK, In vivo PK
Nationell ämneskategori
Farmaceutiska vetenskaper
Identifikatorer
urn:nbn:se:uu:diva-136039 (URN)10.1016/j.bmcl.2010.05.029 (DOI)000279258800001 ()
Tillgänglig från: 2010-12-09 Skapad: 2010-12-09 Senast uppdaterad: 2018-01-12Bibliografiskt granskad
2. Achiral Pyrazinone-Based Inhibitors of the Hepatitis C Virus NS3 Protease and Drug-Resistant Variants with Elongated Substituents Directed Toward the S2 Pocket
Öppna denna publikation i ny flik eller fönster >>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 (Engelska)Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 57, nr 5, s. 1790-1801Artikel i tidskrift (Refereegranskat) 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.

Nationell ämneskategori
Läkemedelskemi
Forskningsämne
Kemi med inriktning mot organisk kemi
Identifikatorer
urn:nbn:se:uu:diva-172003 (URN)10.1021/jm301887f (DOI)000333005800011 ()
Tillgänglig från: 2012-03-31 Skapad: 2012-03-31 Senast uppdaterad: 2018-01-12Bibliografiskt granskad
3. Discovery of pyrazinone based compounds that potently inhibit the drug resistant enzyme variant R155K of the hepatitis C virus NS3 protease
Öppna denna publikation i ny flik eller fönster >>Discovery of pyrazinone based compounds that potently inhibit the drug resistant enzyme variant R155K of the hepatitis C virus NS3 protease
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2016 (Engelska)Ingår i: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 24, nr 12, s. 2603-2620Artikel i tidskrift (Refereegranskat) 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.

Nyckelord
Hepatitis C virus; Drug resistance; Pyrazinone; NS3 protease inhibitors; R155K
Nationell ämneskategori
Organisk kemi
Forskningsämne
Läkemedelskemi
Identifikatorer
urn:nbn:se:uu:diva-243315 (URN)10.1016/j.bmc.2016.03.066 (DOI)000376727800002 ()27160057 (PubMedID)
Forskningsfinansiär
Vetenskapsrådet, D0571301
Tillgänglig från: 2015-02-08 Skapad: 2015-02-08 Senast uppdaterad: 2017-12-04Bibliografiskt granskad
4. Efficient and Selective Palladium-Catalysed C-3 Urea Couplings to 3,5-Dichloro-2(1H)-pyrazinones
Öppna denna publikation i ny flik eller fönster >>Efficient and Selective Palladium-Catalysed C-3 Urea Couplings to 3,5-Dichloro-2(1H)-pyrazinones
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2015 (Engelska)Ingår i: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, nr 5, s. 978-986Artikel i tidskrift (Refereegranskat) 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.

Nationell ämneskategori
Organisk kemi
Forskningsämne
Kemi med inriktning mot organisk kemi; Läkemedelskemi
Identifikatorer
urn:nbn:se:uu:diva-243254 (URN)10.1002/ejoc.201403405 (DOI)000349391700009 ()
Tillgänglig från: 2015-02-06 Skapad: 2015-02-06 Senast uppdaterad: 2017-12-04Bibliografiskt granskad
5. Palladium-catalyzed carbonylation of aryl iodides with sulfinamides
Öppna denna publikation i ny flik eller fönster >>Palladium-catalyzed carbonylation of aryl iodides with sulfinamides
(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nyckelord
palladium
Nationell ämneskategori
Organisk kemi
Forskningsämne
Läkemedelskemi; Kemi med inriktning mot organisk kemi
Identifikatorer
urn:nbn:se:uu:diva-243257 (URN)
Tillgänglig från: 2015-02-06 Skapad: 2015-02-06 Senast uppdaterad: 2015-03-11

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