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Design and Synthesis of Acyclic and Macrocyclic Peptidomimetics as Inhibitors of the Hepatitis C Virus NS3 Protease
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Hepatitis C is a blood-borne disease affecting 130-170 million people worldwide. The causative agent, hepatitis C virus (HCV), infects the liver and is the major reason for chronic liver disease worldwide. The HCV NS3 protease, a key enzyme in the virus replication cycle, has been confirmed to be an important target for drug development. With the recent release of two HCV NS3 protease inhibitors onto the market and an arsenal of inhibitors in clinical trials, there are now hopes of finally combating the disease. However, the success of treatment relies heavily on the ability to overcome the emergence of drug-resistant forms of the protease.

The main focus of this thesis was on designing and synthesizing novel inhibitors of the NS3 protease with a unique resistance profile. Efforts were also made to decrease the peptide character of the compounds, with the long-term goal of making them into more drug-like compounds. Special attention was devoted to developing inhibitors based on a phenylglycine in the P2 position, instead of the highly optimized and commonly used P2 proline. Around ninety acyclic and macrocyclic inhibitors have been synthesized and biochemically evaluated. P2 pyrimidinyloxy phenylglycine was successfully combined with an aromatic P1 moiety and alkenylic P1´ elongations, yielding a distinct class of HCV NS3 protease inhibitors. Macrocyclization was performed in several directions of the inhibitors via ring-closing metathesis. Only the macrocyclization between the P3-P1´ residues was successful in terms of inhibitory potency, which suggests that the elongated P1-P1´ residue is oriented towards the P3 side chain. The metathesis reaction was found to be significantly more dependent on the substrate than on the reaction conditions. It was also found that the P3 truncated inhibitors were able to retain good inhibitory potency, which initiated the synthesis and evaluation of a series of P2-P1´ inhibitors. The potential of the P3-P1´cyclized inhibitor and the smaller, acyclic P2-P1´ as new potential drug leads remains to be determined through pharmacokinetic profiling. Gratifyingly, all the inhibitors evaluated on A156T and D168V substituted enzyme variants were able to retain inhibitory potency towards these as compared to wild-type inhibition.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2012. , 98 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 152
Keyword [en]
hepatitis C virus, HCV, NS3 protease inhibitor, structure-activity relationship, phenylglycine, ring-closing metathesis
National Category
Organic Chemistry
Research subject
Medicinal Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-163361ISBN: 978-91-554-8243-5 (print)OAI: oai:DiVA.org:uu-163361DiVA: diva2:464055
Public defence
2012-02-03, B41, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2012-01-13 Created: 2011-12-11 Last updated: 2012-01-16Bibliographically approved
List of papers
1. Hepatitis C Virus NS3 Protease Inhibitors Comprising a Novel Aromatic P1 Moiety
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, 2955-2967 p.Article 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.

Keyword
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
2. Improved P2 phenylglycine-based hepatitis C virus NS3 protease inhibitors with alkenylic prime-side substituents
Open this publication in new window or tab >>Improved P2 phenylglycine-based hepatitis C virus NS3 protease inhibitors with alkenylic prime-side substituents
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2010 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 18, no 14, 5413-5424 p.Article in journal (Refereed) Published
Abstract [en]

Phenylglycine has proved to be a useful P2 residue in HCV NS3 protease inhibitors. A novel pi-pi-interaction between the phenylglycine and the catalytic H57 residue of the protease is postulated. We hypothesized that the introduction of a vinyl on the phenylglycine might strengthen this pi-pi-interaction. Thus, herein is presented the synthesis and inhibitory potency of a series of acyclic vinylated phenylglycine-based HCV NS3 protease inhibitors. Surprisingly, inhibitors based on both D- and L-phenylglycine were found to be effective inhibitors, with a slight preference for the d-epimers. Furthermore, prime-side alkenylic extension of the C-terminal acylsulfonamide group gave significantly improved inhibitors with potencies in the nanomolar range (approximately 35 nM), potencies which were retained on mutant variants of the protease.

Keyword
HCV, Protease inhibitors, Peptidomimetics, Phenylglycine, Resistance, Alkenylic acylsulfonamides
National Category
Natural Sciences Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-129431 (URN)10.1016/j.bmc.2010.05.027 (DOI)000279744700060 ()20541424 (PubMedID)
Available from: 2010-08-15 Created: 2010-08-15 Last updated: 2017-12-12Bibliographically approved
3. P2-P1 ' macrocyclization of P2 phenylglycine based HCV NS3 protease inhibitors using ring-closing metathesis
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, 4917-4927 p.Article 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.

Keyword
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
4. Diversely Vinylated Acyclic Pyrimidinyloxyphenylglycine-based Inhibitors of the HCV NS3 Protease and Corresponding Macrocycles: Beneficial use of an Aromatic P1 moiety
Open this publication in new window or tab >>Diversely Vinylated Acyclic Pyrimidinyloxyphenylglycine-based Inhibitors of the HCV NS3 Protease and Corresponding Macrocycles: Beneficial use of an Aromatic P1 moiety
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(English)Manuscript (preprint) (Other academic)
National Category
Organic Chemistry
Research subject
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-163354 (URN)
Available from: 2011-12-11 Created: 2011-12-11 Last updated: 2012-01-16
5. Novel Peptidomimetic HCV NS3 Protease Inhibitors Spanning the P2–P1´ Region
Open this publication in new window or tab >>Novel Peptidomimetic HCV NS3 Protease Inhibitors Spanning the P2–P1´ Region
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Organic Chemistry
Research subject
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-163356 (URN)
Available from: 2011-12-11 Created: 2011-12-11 Last updated: 2012-01-16

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