Search: onr:"swepub:oai:DiVA.org:uu-172003" >
Achiral Pyrazinone-...
Achiral Pyrazinone-Based Inhibitors of the Hepatitis C Virus NS3 Protease and Drug-Resistant Variants with Elongated Substituents Directed Toward the S2 Pocket
-
- Gising, Johan, 1981- (author)
- Uppsala universitet,Avdelningen för organisk farmaceutisk kemi
-
- Belfrage, Anna Karin (author)
- Uppsala universitet,Avdelningen för organisk farmaceutisk kemi
-
- Alogheli, Hiba (author)
- Uppsala universitet,Avdelningen för organisk farmaceutisk kemi
-
show more...
-
- Ehrenberg, Angelica (author)
- Uppsala universitet,Institutionen för kemi - BMC
-
- Åkerblom, Eva (author)
- Uppsala universitet,Avdelningen för organisk farmaceutisk kemi
-
- Svensson, Richard (author)
- Uppsala universitet,Institutionen för farmaci
-
- Artursson, Per (author)
- Uppsala universitet,Institutionen för farmaci
-
- Anders, Karlén (author)
- Uppsala universitet,Avdelningen för organisk farmaceutisk kemi
-
- Danielsson, U. Helena (author)
- Uppsala universitet,Institutionen för kemi - BMC
-
- Larhed, Mats (author)
- Uppsala universitet,Avdelningen för organisk farmaceutisk kemi
-
- Sandström, Anja (author)
- Uppsala universitet,Avdelningen för organisk farmaceutisk kemi
-
show less...
-
(creator_code:org_t)
- 2013-04-02
- 2014
- English.
-
In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 57:5, s. 1790-1801
- Related links:
-
http://pubs.acs.org/...
-
show more...
-
https://doi.org/10.1...
-
https://urn.kb.se/re...
-
https://doi.org/10.1...
-
show less...
Abstract
Subject headings
Close
- Herein we describe the design, synthesis, inhibitory potency, and pharmacokinetic properties of a novel class of achiral peptidomimetic HCV NS3 protease inhibitors. The compounds are based on a dipeptidomimetic pyrazinone glycine P3P2 building block in combination with an aromatic acyl sulfonamide in the P1P1′ position. Structure–activity relationship data and molecular modeling support occupancy of the S2 pocket from elongated R6 substituents on the 2(1H)-pyrazinone core and several inhibitors with improved inhibitory potency down to Ki = 0.11 μM were identified. A major goal with the design was to produce inhibitors structurally dissimilar to the di- and tripeptide-based HCV protease inhibitors in advanced stages of development for which cross-resistance might be an issue. Therefore, the retained and improved inhibitory potency against the drug-resistant variants A156T, D168V, and R155K further strengthen the potential of this class of inhibitors. A number of the inhibitors were tested in in vitro preclinical profiling assays to evaluate their apparent pharmacokinetic properties. The various R6 substituents were found to have a major influence on solubility, metabolic stability, and cell permeability.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medicinal Chemistry (hsv//eng)
Keyword
- Chemistry with specialization in Organic Chemistry
- Kemi med inriktning mot organisk kemi
Publication and Content Type
- ref (subject category)
- art (subject category)
Find in a library
To the university's database
- By the author/editor
-
Gising, Johan, 1 ...
-
Belfrage, Anna K ...
-
Alogheli, Hiba
-
Ehrenberg, Angel ...
-
Åkerblom, Eva
-
Svensson, Richar ...
-
show more...
-
Artursson, Per
-
Anders, Karlén
-
Danielsson, U. H ...
-
Larhed, Mats
-
Sandström, Anja
-
show less...
- About the subject
-
- MEDICAL AND HEALTH SCIENCES
-
MEDICAL AND HEAL ...
-
and Basic Medicine
-
and Medicinal Chemis ...
- Articles in the publication
-
Journal of Medic ...
- By the university
-
Uppsala University