Highly potent macrocyclic BACE-1 inhibitors incorporating a hydroxyethylamine core: Design, synthesis and X-ray crystal structures of enzyme inhibitor complexes
2012 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 29, no 14, 4377-4389 p.Article in journal (Refereed) Published
A series of P1-P3 linked macrocyclic BACE-1 inhibitors containing a hydroxyethylamine (HEA) isostere scaffold has been synthesized. All inhibitors comprise a toluene or N-phenylmethanesulfonamide P2 moiety. Excellent BACE-1 potencies, both in enzymatic and cell-based assays, were observed in this series of target compounds, with the best candidates displaying cell-based IC50 values in the low nanomolar range. As an attempt to improve potency, a phenyl substituent aiming at the S3 subpocket was introduced in the macrocyclic ring. X-ray analyses were performed on selected compounds, and enzyme-inhibitor interactions are discussed.
Place, publisher, year, edition, pages
Elsevier, 2012. Vol. 29, no 14, 4377-4389 p.
Alzheimer’s disease; BACE-1 inhibition; Macrocycles; Hydroxyethylamine (HEA) isostere
IdentifiersURN: urn:nbn:se:liu:diva-76172DOI: 10.1016/j.bmc.2012.05.039ISI: 000305952500023OAI: oai:DiVA.org:liu-76172DiVA: diva2:512918
On the day of the defence day the status of this article was Manuscript.2012-03-292012-03-292012-09-18Bibliographically approved