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Novel potent macrocyclic inhibitors of the hepatitis C virus NS3 protease: use of cyclopentane and cyclopentene P2-motifs
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
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2007 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, 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 Ki value of 0.41 nM and an EC50 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.

Place, publisher, year, edition, pages
2007. Vol. 15, no 22, 7184-7202 p.
Keyword [en]
Cyclopentane and Cyclopentene derived P2 templates, HCV, Macrocyclic inhibitors, NS3 protease
National Category
Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-17095DOI: 10.1016/j.bmc.2007.07.027ISI: 000250324900030PubMedID: 17845856OAI: oai:DiVA.org:uu-17095DiVA: diva2:44866
Available from: 2008-06-16 Created: 2008-06-16 Last updated: 2011-01-20Bibliographically approved
In thesis
1. Design and Synthesis of Aspartic and Serine Protease Inhibitors: Targeting the BACE-1 and the HCV NS3 Protease
Open this publication in new window or tab >>Design and Synthesis of Aspartic and Serine Protease Inhibitors: Targeting the BACE-1 and the HCV NS3 Protease
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis describes work done to design and synthesize protease inhibitors, with the intention of developing therapeutic agents for Alzheimer’s disease (AD) and the chronic liver condition caused by infection of the hepatitis C virus (HCV). AD is the most common form of dementia, and HCV infection is the primary reason for liver transplantation in industrialized countries. Today, these two illnesses affect 24 and 170 million people, respectively. It has been shown that the human aspartic protease BACE-1 plays an important role in the development of AD, and thus inhibition of BACE-1 may offer a way to improve the quality of life of individuals afflicted with the disease. Furthermore, it is known that the serine protease NS3 is a vital component in the replication of HCV.

Several novel potent BACE-1 inhibitors encompassing different transition state mimics were prepared. First, a hydroxyethylene moiety encompassing a secondary hydroxyl group was evaluated as a transition state analogue, producing inhibitors in the low nanomolar range. Various tertiary hydroxyl isosteres were also investigated as the central core, with the aim of shielding the pivotal hydroxyl group. These transition state isosteres consisted of tertiary hydroxyl analogues of previously used secondary hydroxyl containing norstatine, statine, and hydroxyethylamine isosteres. Several tertiary hydroxyl-containing inhibitors were found to be active in the low micromolar range. In addition, two inhibitors were co-crystallized with the BACE-1 enzyme to provide X-ray crystal structures, which furnished valuable binding information for further design of improved BACE-1 inhibitors.

The goal in the HCV NS3 protease inhibitor project was to design, synthesize and evaluate a novel hydroxycyclopentene bioisostere to the previously used acyl-hydroxyproline moiety. The investigation revealed that it was possible to synthesize inhibitors containing this new bioisostere that were potent in the low nanomolar range. Further optimization by rigidification of the most active inhibitor resulted in equipotent macrocyclic compounds.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 71 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 108
Alzheimer's disease, BACE-1, transition state mimetic, tertiary hydroxyl group, hydroxyethylene, statine, hydroxyethylamine, hepatitis C, HCV NS3, bioisostere, protease inhibitor.
National Category
Medicinal Chemistry
Research subject
Medicinal Chemistry
urn:nbn:se:uu:diva-108985 (URN)978-91-554-7623-6 (ISBN)
Public defence
2009-11-20, B42, Biomedical Centre (BMC), Husargatan 3, Uppsala, 09:15 (English)
Available from: 2009-10-29 Created: 2009-10-06 Last updated: 2011-03-02Bibliographically approved

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