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Design and Synthesis of Inhibitors Targeting the Hepatitis C Virus NS3 Serine Protease and the Aspartic Protease BACE-1
Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis describes the synthesis of molecules designed to inhibit the hepatitis C virus (HCV) NS3 serine protease and the human aspartic protease BACE-1, and it also reports the structure-activity relationships between potential inhibitors and the targeted enzymes. In addition, consideration is given to the class of enzymes known as proteases, as well as the question of why such enzymes can be regarded as suitable targets for developing drugs to combat diseases in general. Some strategies used to design protease inhibitors and the desired properties of such potential drug candidates are also briefly examined.

Infection with HCV gives rise to a predominantly chronic disease that causes severe liver damage and ultimately leads to cirrhosis and liver cancer, and hence it represents the main factor underlying most of the liver transplants in the developed world. The HCV NS3 serine protease is essential for replication of the virus, and it has become one of the most widely exploited targets for developing anti-HCV inhibitors. The results presented here concern the design and synthesis of linear and macrocyclic NS3 protease inhibitors containing a novel trisubstituted cyclopentane moiety as an N-acyl-(4R)-hydroxyproline bioisostere. Several highly potent compounds were evaluated, including inhibitors with Ki and replicon EC50 values in the subnanomolar and the low nanomolar range, respectively.

Alzheimer’s disease is a fatal neurodegenerative disorder of the brain. It is characterized by loss of memory and cognition, and is associated with accumulation of plaques and tangles that cause serious impairment and functional decline of brain tissues. The plaques consist mainly of amyloid-β fragments that are generated through two cleavages of amyloid precursor protein (APP). The enzyme responsible for the initial cleavage is the aspartic protease BACE-1 (beta-site APP-cleaving enzyme), which was explored in the current studies as a pharmaceutical target. The synthetic work comprised development of two series of BACE-1 inhibitors with different central core isosteres; a statine-based and a hydroxyethylene-based series. Highly potent inhibitors were produced by varying the substituents coupled to the statine-based central core. X-ray crystallography and molecular modeling enabled analysis of the binding properties of these compounds. In the second series a hydroxyethylene central core was decorated with more advanced P1 substituents with the aim of increasing the binding interactions with the S1 site. This resulted in inhibitors with more drug-like properties and activities in the low micromolar range.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2009. , 74 p.
Series
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1253
National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:liu:diva-17850ISBN: 978-91-7393-642-2 (print)OAI: oai:DiVA.org:liu-17850DiVA: diva2:212508
Public defence
2009-05-15, Hörsal Planck, Campus Valla, Linköpings universitet, Linköping, 13:15 (English)
Opponent
Supervisors
Available from: 2009-04-22 Created: 2009-04-22 Last updated: 2014-01-09Bibliographically approved
List of papers
1. Potent inhibitors of the hepatitis C virus NS3 protease: use of a novel P2 cyclopentane-derived template
Open this publication in new window or tab >>Potent inhibitors of the hepatitis C virus NS3 protease: use of a novel P2 cyclopentane-derived template
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2006 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 14, no 15, 5136-5151 p.Article in journal (Refereed) Published
Abstract [en]

The HCV NS3 protease is essential for replication of the hepatitis C virus (HCV) and therefore constitutes a promising new drug target for anti-HCV therapy. Several potent and promising HCV NS3 protease inhibitors, some of which display low nanomolar activities, were identified from a series of novel inhibitors incorporating a trisubstituted cyclopentane dicarboxylic acid moiety as a surrogate for the widely used N-acyl-(4R)-hydroxyproline in the P2 position.

Keyword
HCV, NS3, Protease inhibitor, Cyclopentane-derived P2 scaffold
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-14308 (URN)10.1016/j.bmc.2006.04.008 (DOI)
Available from: 2007-02-21 Created: 2007-02-21 Last updated: 2012-12-06Bibliographically approved
2. Novel potent macrocyclic inhibitors of the hepatitis C virus NS3 protease: use of cyclopentane and cyclopentene P2-motifs.
Open this publication in new window or tab >>Novel potent macrocyclic inhibitors of the hepatitis C virus NS3 protease: use of cyclopentane and cyclopentene P2-motifs.
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2007 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, Vol. 15, no 22, 7184-7202 p.Article in journal (Refereed) Published
Abstract [en]

Several highly potent novel HCV NS3 protease inhibitors have been developed from two inhibitor series containing either a P2 trisubstituted macrocyclic cyclopentane- or a P2 cyclopentene dicarboxylic acid moiety as surrogates for the widely used N-acyl-(4R)-hydroxyproline in the P2 position. These inhibitors were optimized for anti HCV activities through examination of different ring sizes in the macrocyclic systems and further by exploring the effect of P4 substituent removal on potency. The target molecules were synthesized from readily available starting materials, furnishing the inhibitor compounds in good overall yields. It was found that the 14-membered ring system was the most potent in these two series and that the corresponding 13-, 15-, and 16-membered macrocyclic rings delivered less potent inhibitors. Moreover, the corresponding P1 acylsulfonamides had superior potencies over the corresponding P1 carboxylic acids. It is noteworthy that it has been possible to develop highly potent HCV protease inhibitors that altogether lack the P4 substituent. Thus the most potent inhibitor described in this work, inhibitor 20, displays a K(i) value of 0.41 nM and an EC(50) value of 9 nM in the subgenomic HCV replicon cell model on genotype 1b. To the best of our knowledge this is the first example described in the literature of a HCV protease inhibitor displaying high potency in the replicon assay and lacking the P4 substituent, a finding which should facilitate the development of orally active small molecule inhibitors against the HCV protease.

National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-17846 (URN)10.1016/j.bmc.2007.07.027 (DOI)17845856 (PubMedID)
Available from: 2009-04-22 Created: 2009-04-22 Last updated: 2009-04-22Bibliographically approved
3. Design, synthesis and SAR of potent statine-based BACE-1 inhibitors: exploration of P1 phenoxy and benzyloxy residues.
Open this publication in new window or tab >>Design, synthesis and SAR of potent statine-based BACE-1 inhibitors: exploration of P1 phenoxy and benzyloxy residues.
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2008 (English)In: Bioorganic & medicinal chemistry, ISSN 1464-3391, Vol. 16, no 21, 9471-9486 p.Article in journal (Refereed) Published
Abstract [en]

Several BACE-1 inhibitors with low nanomolar level activities, encompassing a statine-based core structure with phenyloxymethyl- and benzyloxymethyl residues in the P1 position, are presented. The novel P1 modification introduced to allow the facile exploration of the S1 binding pocket of BACE-1, delivered highly promising inhibitors.

Keyword
Alzheimer’s disease, BACE-1 inhibitors, P1 modifications, Peptidomimetics
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-17848 (URN)10.1016/j.bmc.2008.09.041 (DOI)18842420 (PubMedID)
Available from: 2009-04-22 Created: 2009-04-22 Last updated: 2009-04-22Bibliographically approved
4. Design and Synthesis of Hydroxyethylene-Based BACE-1 Inhibitors Incorporating Extended P1 Substituents
Open this publication in new window or tab >>Design and Synthesis of Hydroxyethylene-Based BACE-1 Inhibitors Incorporating Extended P1 Substituents
(English)Manuscript (Other academic)
Abstract [en]

BACE-1 inhibitors with a hydroxyetylene central core, comprising a methoxy residue in the P1´ position, are presented. Extended P1 substituents were introduced with the aim to explore possible interactions with the S1-S3 pocket. Incorporation of the more advanced P1 substituents produced promising inhibitors in the low micromolar range.

National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-17849 (URN)
Available from: 2009-04-22 Created: 2009-04-22 Last updated: 2014-01-09Bibliographically approved

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Bäck, Marcus

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