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Improved P2 phenylg...
Improved P2 phenylglycine-based hepatitis C virus NS3 protease inhibitors with alkenylic prime-side substituents
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- Lampa, Anna (author)
- Uppsala universitet,Avdelningen för organisk farmaceutisk kemi
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- Ehrenberg, Angelica E. (author)
- Uppsala universitet,Biokemi
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- Gustafsson, Sofia S. (author)
- Uppsala universitet,Biokemi
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- Vema, Aparna (author)
- Uppsala universitet,Avdelningen för organisk farmaceutisk kemi
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- Åkerblom, Eva (author)
- Uppsala universitet,Avdelningen för organisk farmaceutisk kemi
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- Lindeberg, Gunnar (author)
- Uppsala universitet,Avdelningen för organisk farmaceutisk kemi
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- Karlén, Anders (author)
- Uppsala universitet,Avdelningen för organisk farmaceutisk kemi
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- Danielson, U. Helena (author)
- Uppsala universitet,Biokemi
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- Sandström, Anja (author)
- Uppsala universitet,Avdelningen för organisk farmaceutisk kemi
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(creator_code:org_t)
- Elsevier BV, 2010
- 2010
- English.
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In: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896 .- 1464-3391. ; 18:14, s. 5413-5424
- Related links:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Subject headings
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- Phenylglycine has proved to be a useful P2 residue in HCV NS3 protease inhibitors. A novel pi-pi-interaction between the phenylglycine and the catalytic H57 residue of the protease is postulated. We hypothesized that the introduction of a vinyl on the phenylglycine might strengthen this pi-pi-interaction. Thus, herein is presented the synthesis and inhibitory potency of a series of acyclic vinylated phenylglycine-based HCV NS3 protease inhibitors. Surprisingly, inhibitors based on both D- and L-phenylglycine were found to be effective inhibitors, with a slight preference for the d-epimers. Furthermore, prime-side alkenylic extension of the C-terminal acylsulfonamide group gave significantly improved inhibitors with potencies in the nanomolar range (approximately 35 nM), potencies which were retained on mutant variants of the protease.
Keyword
- HCV
- Protease inhibitors
- Peptidomimetics
- Phenylglycine
- Resistance
- Alkenylic acylsulfonamides
- PHARMACY
- FARMACI
- NATURAL SCIENCES
- NATURVETENSKAP
Publication and Content Type
- ref (subject category)
- art (subject category)
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