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Design and Synthesis of Inhibitors Targeting the Hepatitis C Virus NS3 Protease: Focus on C-Terminal Acyl Sulfonamides
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
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. , p. 79
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 53
Keywords [en]
Pharmaceutical chemistry, hepatitis C virus, HCV, NS3 protease inhibitor, acyl sulfonamide, bioisostere, palladium, carbonylation, microwave, molybdenum hexacarbonyl
Keywords [sv]
Farmaceutisk kemi
Identifiers
URN: urn:nbn:se:uu:diva-7814ISBN: 978-91-554-6862-0 (print)OAI: oai:DiVA.org:uu-7814DiVA, id: diva2:170077
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
List of papers
1. Exploration of acyl sulfonamides as carboxylic acid replacements in protease inhibitors of the hepatitis C virus full-length NS3
Open this publication in new window or tab >>Exploration of acyl sulfonamides as carboxylic acid replacements in protease inhibitors of the hepatitis C virus full-length NS3
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2006 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 14, no 2, p. 544-559Article in journal (Refereed) Published
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-75612 (URN)10.1016/j.bmc.2005.08.045 (DOI)16213143 (PubMedID)
Available from: 2006-03-04 Created: 2006-03-04 Last updated: 2018-01-14Bibliographically approved
2. Evaluation of a diverse set of potential P1 carboxylic acid bioisosteres in hepatitis C virus NS3 protease inhibitors
Open this publication in new window or tab >>Evaluation of a diverse set of potential P1 carboxylic acid bioisosteres in hepatitis C virus NS3 protease inhibitors
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2007 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 15, no 12, p. 4057-4068Article in journal (Refereed) Published
Abstract [en]

There is an urgent need for more efficient therapies for people infected with hepatitis C virus (HCV). HCV NS3 protease inhibitors have shown proof-of-concept in clinical trials, which make the virally encoded NS3 protease an attractive drug target. Product-based NS3 protease inhibitors comprising a P1 C-terminal carboxylic acid have shown to be effective and we were interested in finding alternatives to this crucial carboxylic acid group. Thus, a series of diverse P1 functional groups with different acidity and with possibilities to form a similar, or an even more powerful, hydrogen bond network as compared to the carboxylic acid were synthesized and incorporated into potential inhibitors of the NS3 protease. Biochemical evaluation of the inhibitors was performed in both enzyme and cell-based assays. Several non-acidic C-terminal groups, such as amides and hydrazides, were evaluated but failed to produce inhibitors more potent than the corresponding carboxylic acid inhibitor. The tetrazole moiety, although of similar acidity to a carboxylic acid, provided an inhibitor with mediocre potencies in both assays. However, the acyl cyanamide and the acyl sulfinamide groups rendered compounds with low nanomolar inhibitory potencies and were more potent than the corresponding carboxylic acid inhibitor in the enzymatic assay. Additionally, results from a pH-study suggest that the P1 C-terminal of the inhibitors comprising a carboxylic acid, an acyl sulfonamide or an acyl cyanamide group binds in a similar mode in the active site of the NS3 protease.

Keywords
Bioisostere, HCV, Hepatitis C, NS3, Protease inhibitor
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-17091 (URN)10.1016/j.bmc.2007.03.089 (DOI)000246870400010 ()17449253 (PubMedID)
Available from: 2008-06-16 Created: 2008-06-16 Last updated: 2018-01-12Bibliographically approved
3. Easy-to-Execute Carbonylations: Microwave Synthesis of Acyl Sulfonamides Using Mo(CO)6 as a Solid Carbon Monoxide Source
Open this publication in new window or tab >>Easy-to-Execute Carbonylations: Microwave Synthesis of Acyl Sulfonamides Using Mo(CO)6 as a Solid Carbon Monoxide Source
2005 (English)In: The Journal of Organic Chemistry, ISSN 0022-3263, Vol. 70, no 8, p. 3094-3098Article in journal (Refereed) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-95747 (URN)
Available from: 2007-04-13 Created: 2007-04-13 Last updated: 2013-07-04Bibliographically approved
4. 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, p. 2955-2967Article 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.

Keywords
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

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