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Investigation of alpha-phenylnorstatine and alpha-benzylnorstatine as transition state isostere motifs in the search for new BACE-1 inhibitors
Uppsala University.
Uppsala University.
Uppsala University.
Uppsala University.
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2011 (English)In: BIOORGANIC and MEDICINAL CHEMISTRY, ISSN 0968-0896, Vol. 19, no 1, 145-155 p.Article in journal (Refereed) Published
Abstract [en]

Inhibition of the BACE-1 protease enzyme has over the recent decade developed into a promising drug strategy for Alzheimer therapy. In this report, more than 20 new BACE-1 protease inhibitors based on alpha-phenylnorstatine, alpha-benzylnorstatine, iso-serine, and beta-alanine moieties have been prepared. The inhibitors were synthesized by applying Fmoc solid phase methodology and evaluated for their inhibitory properties. The most potent inhibitor, tert-alcohol containing (R)-12 (IC50 = 0.19 mu M) was co-crystallized in the active site of the BACE-1 protease, furnishing a novel binding mode in which the N-terminal amine makes a hydrogen bond to one of the catalytic aspartic acids.

Place, publisher, year, edition, pages
Elsevier Science B.V., Amsterdam. , 2011. Vol. 19, no 1, 145-155 p.
Keyword [en]
Alzheimers disease, BACE-1 inhibitors, tert-Hydroxyl, Transition state mimic, alpha-Phenylnorstatine, alpha-Benzylnorstatine
National Category
Engineering and Technology
URN: urn:nbn:se:liu:diva-65957DOI: 10.1016/j.bmc.2010.11.042ISI: 000285724800014OAI: diva2:400662
Available from: 2011-02-28 Created: 2011-02-28 Last updated: 2011-02-28

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Rosenqvist, Åsa
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Organic Chemistry The Institute of Technology
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ReferencesLink to record
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