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Hepatitis C Virus NS3 Protease Inhibitors Comprising a Novel Aromatic P1 Moiety
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 Biochemistry and Organic Chemistry.
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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.

Place, publisher, year, edition, pages
2008. Vol. 16, no 6, 2955-2967 p.
Keyword [en]
HCV, NS3, protease inhibitor, carbonylation, acyl sulfonamide, palladium
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-95748DOI: 10.1016/j.bmc.2007.12.041ISI: 000255127700023PubMedID: 18194867OAI: oai:DiVA.org:uu-95748DiVA: diva2:170076
Available from: 2007-04-13 Created: 2007-04-13 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Design and Synthesis of Inhibitors Targeting the Hepatitis C Virus NS3 Protease: Focus on C-Terminal Acyl Sulfonamides
Open this publication in new window or tab >>Design and Synthesis of Inhibitors Targeting the Hepatitis C Virus NS3 Protease: Focus on C-Terminal Acyl Sulfonamides
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Hepatitis C is a global health problem that affects approximately 120–180 million people. This viral infection causes serious liver diseases and the therapy available suffers from low efficiency and severe side effects. Consequently, there is a huge unmet medical need for new therapeutic agents to combat the hepatitis C virus (HCV). Inhibition of the viral NS3 protease has recently emerged as a promising approach to defeat this infection, and the first HCV NS3 protease inhibitors have now entered clinical trials.

In this project, several novel HCV NS3 protease inhibitors have been designed, synthesized and biochemically evaluated. Inhibitors with various P1 C-terminal functional groups intended as potential bioisosteres to the carboxylic acid found in product-based inhibitors have been revealed. Special focus has been placed on establishing structure–activity relationships of inhibitors containing the promising P1 C-terminal acyl sulfonamide group. The properties of the acyl sulfonamide functionality that are important for producing potent inhibitors have been identified. In addition, the advantages of the acyl sulfonamide group compared to the carboxylic acid have been demonstrated in both enzymatic and cell-based assays.

Besides the acyl sulfonamide functionality, the acyl cyanamide and the acyl sulfinamide groups have been identified as new carboxylic acid bioisosteres in HCV NS3 protease inhibitors.

The synthetic work included the development of a fast and convenient methodology for the preparation of aryl acyl sulfonamides. The use of microwave heating and Mo(CO)6 as a solid carbon monoxide source provided aryl acyl sulfonamides from aryl halides in excellent yields. This method was subsequently used in the decoration of novel HCV NS3 protease inhibitors comprising a non-natural P1 moiety. This new class of compounds can be used as lead structures in a future optimization process aimed at producing more drug-like HCV NS3 protease inhibitors.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 79 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 53
Keyword
Pharmaceutical chemistry, hepatitis C virus, HCV, NS3 protease inhibitor, acyl sulfonamide, bioisostere, palladium, carbonylation, microwave, molybdenum hexacarbonyl, Farmaceutisk kemi
Identifiers
urn:nbn:se:uu:diva-7814 (URN)978-91-554-6862-0 (ISBN)
Public defence
2007-05-04, B22, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2007-04-13 Created: 2007-04-13 Last updated: 2009-11-30Bibliographically approved
2. Design and Synthesis of Acyclic and Macrocyclic Peptidomimetics as Inhibitors of the Hepatitis C Virus NS3 Protease
Open this publication in new window or tab >>Design and Synthesis of Acyclic and Macrocyclic Peptidomimetics as Inhibitors of the Hepatitis C Virus NS3 Protease
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
hepatitis C virus, HCV, NS3 protease inhibitor, structure-activity relationship, phenylglycine, ring-closing metathesis
National Category
Organic Chemistry
Research subject
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-163361 (URN)978-91-554-8243-5 (ISBN)
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

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Åkerblom, EvaDanielson, U. HelenaSandström, Anja

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