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Solid-phase parallel synthesis and SAR of 4-amidofuran-3-one inhibitors of cathepsin S: Effect of sulfonamides P3 substituents on potency and selectivity.
Stockholm University, Faculty of Science, Department of Organic Chemistry.
Stockholm University, Faculty of Science, Department of Organic Chemistry. (Bertil Samuelsson)
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2009 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 17, no 3, 1307-1324 p.Article in journal (Refereed) Published
Abstract [en]

Highly potent and selective 4-amidofuran-3-one inhibitors of cathepsin S are described. The synthesis and structure–activity relationship of a series of inhibitors with a sulfonamide moiety in the P3 position is presented. Several members of the series show sub-nanomolar inhibition of the target enzyme as well as an excellent selectivity profile and good cellular potency. Molecular modeling of the most interesting inhibitors describes interactions in the extended S3 pocket and explains the observed selectivity towards cathepsin K.

Place, publisher, year, edition, pages
Elsevier , 2009. Vol. 17, no 3, 1307-1324 p.
Keyword [en]
Cysteine protease, cathepsin S, cathepsin K, reversible covalent inhibition
National Category
Medicinal Chemistry
Research subject
Organic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-35087DOI: 10.1016/j.bmc.2008.12.020OAI: oai:DiVA.org:su-35087DiVA: diva2:286553
Available from: 2010-01-15 Created: 2010-01-14 Last updated: 2017-12-12Bibliographically approved
In thesis
1. Design and Synthesis of Amine Building Blocks and Protease Inhibitors
Open this publication in new window or tab >>Design and Synthesis of Amine Building Blocks and Protease Inhibitors
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The first part of this thesis addresses the design and synthesis of amine building blocks accomplished by applying two different synthetic procedures, both of which were developed using solid-phase chemistry. Chapter 1 presents the first of these methods, entailing a practical solid-phase parallel synthesis route to N-monoalkylated aminopiperidines and aminopyrrolidines achieved by selective reductive alkylation of primary and/or secondary amines. Solid-phase NMR spectroscopy was used to monitor the reactions for which a new pulse sequence was developed. The second method, reported in Chapter 2, involves a novel approach to the synthesis of secondary amines starting from reactive alkyl halides and azides. The convenient solid-phase protocol that was devised made use of the Staudinger reaction in order to accomplish highly efficient alkylations of N-alkyl phosphimines or N-aryl phosphimines with reactive alkyl halides.

The second part of the thesis describes the design and synthesis of three classes of protease inhibitors targeting the cysteine proteases cathepsins S and K, and the serine protease hepatitis C virus (HCV) NS3 protease. Chapter 4 covers the design, solid-phase synthesis, and structure-activity relationships of 4-amidofurane-3-one P1-containing inhibitors of cathepsin S and the effects of P3 sulfonamide groups on the potency and selectivity towards related cathepsin proteases. This work resulted in the discovery of highly potent and selective inhibitors of cathepsin S. Two parallel solid-phase approaches to the synthesis of a series of aminoethylamide inhibitors of cathepsin K are presented in Chapter 5. Finally, Chapter 6 reports peptide-based HCV NS3 protease inhibitors containing a non-electrophilic allylic alcohol moiety as P1 group and also outlines efforts to incorporate this new template into low-molecular-weight drug-like molecules.

Place, publisher, year, edition, pages
Stockholm: Institutionen för organisk kemi, 2008. 77 p.
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-8038 (URN)978-91-7155-690-5 (ISBN)
Public defence
2008-10-03, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 12 A, Stockholm, 10:00 (English)
Opponent
Supervisors
Available from: 2008-09-11 Created: 2008-08-25 Last updated: 2010-01-15Bibliographically approved
2. Design & Synthesis of Protein Interacting Affinity Ligands and Protease Inhibitors
Open this publication in new window or tab >>Design & Synthesis of Protein Interacting Affinity Ligands and Protease Inhibitors
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

There is a growing need of both protein drugs and synthetic drugs in the fight against many life-threatening diseases. The first part of this thesis deals with the design and synthesis of high affinity binding ligands for the purification of protein drugs. The second part describes design and synthesis of protease inhibitors targeting the cysteine protease cathepsin S and the serine protease hepatitis C NS3/4A.

In work with parallel synthesis of new affinity chromatography ligands, indole was used as the scaffold for both solid phase and solution phase syntheses. A library of 1,3-disubstituted indoles was prepared via an iterative Mannich reaction sequence. The first Mannich reaction provided 3-aminomethylindoles, while the second Mannich reaction introduced an additional aminomethyl group at the N1 position of the indole ring. A library of 25 substituted indoles was prepared in moderate to good yields and purity.

Inhibition of the cysteine protease cathepsin S is an attractive target for drug development of inhibitors having potential for regulation of autoimmune diseases and allergic disorders. Syntheses targeting the cysteine protease cathepsin S were performed by a solid phase approach. The structure-activity-relationships (SAR) of variations in the P3 sulfonamide part of 4-amidofuran-3-one inhibitors are presented. Several highly potent inhibitors were found, in both enzyme and cellular assays.

The hepatitis C virus (HCV), causes a chronic liver condition which can lead to cirrhosis and liver cancer. The  serine protease hepatitis C NS3/4A is a promising target for development of HCV drugs. In the syntheses of novel HCV NS3/4A inhibitors, four new P2 substituents were first incorporated on a proline-based linear scaffold. The most potent P2 substituent, quinazoline, was evaluated in a larger study yielding more rigidified cyclopentane-based macrocyclic inhibitors. The SAR exercise resulted in several inhibitors with excellent potency in the low nanomolar range.

Place, publisher, year, edition, pages
Stockholm: Department of Organic Chemistry, Stockholm University, 2010. 96 p.
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-35292 (URN)978-91-7155-994-4 (ISBN)
Public defence
2010-02-11, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16B, Stockholm, 13:00 (English)
Opponent
Supervisors
Note
At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: ManuscriptAvailable from: 2010-01-20 Created: 2010-01-15 Last updated: 2010-01-15Bibliographically approved

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