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Design and Synthesi...
Design and Synthesis of BACE-1 Inhibitors Containing a New Hydroxyethylene (HE) Scaffold: Potent activities in a cellular assay
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- Adrian Meredith, Jenny, 1971- (author)
- Stockholms universitet,Institutionen för organisk kemi,Bertil Samuelsson
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- Björklund, Catarina, 1981- (author)
- Stockholms universitet,Institutionen för organisk kemi,Bertil Samuelsson
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- Adolfsson, Hans (author)
- Stockholms universitet,Institutionen för organisk kemi,Hans Adolfsson
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Edlund, Michael (author)
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Jansson, Katarina (author)
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Lindberg, Jimmy (author)
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Vrang, Lotta (author)
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- Hallberg, Anders (author)
- Institutionen för läkemedelskemi, Uppsala universitet
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Rosenquist, Åsa (author)
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- Samuelsson, Bertil (author)
- Stockholms universitet,Institutionen för organisk kemi
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(creator_code:org_t)
- English.
- Related links:
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https://urn.kb.se/re...
Abstract
Subject headings
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- In a preceding report from our group we disclosed the development of a novel HE transition state isostere with a difluorophenoxymethyl side chain in the P1 position and a methoxy group in the P1’ position furnishing highly potent inhibitors of BACE-1 (i.e. lead compound 1), which moreover exhibit very promising selectivity over cathepsin D. In a continuation of this work with the aim at improving on the cell-based activity and pharmacokinetic properties, we have further developed the SAR for the P1 side chain of inhibitor 1 whereby the P1 side chain oxygen has been substituted for an amine, a carbon or a bond. The chemistry developed for the previous HE inhibitor structure 1 has now been extended to readily accommodate the introduction of new P1 side chains into this new HE scaffold. These modifications have given rise to several highly potent inhibitors where the most potent displayed a BACE-1 Ki value of 0.2 nM and a cell-based Aβ40 IC50 value of 9 nM. Thus, regarding the enzyme inhibition in the cell assay a more than 600-fold improvement compared to compound 1 was achieved via minor structural alterations.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medicinal Chemistry (hsv//eng)
Keyword
- Pharmaceutical chemistry
- Läkemedelskemi
- organisk kemi
- Organic Chemistry
Publication and Content Type
- vet (subject category)
- ovr (subject category)
To the university's database
- By the author/editor
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Adrian Meredith, ...
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Björklund, Catar ...
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Adolfsson, Hans
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Edlund, Michael
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Jansson, Katarin ...
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Lindberg, Jimmy
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show more...
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Vrang, Lotta
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Hallberg, Anders
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Rosenquist, Åsa
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Samuelsson, Bert ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Medicinal Chemis ...
- By the university
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Stockholm University