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Bioorg Med Chem Lett. 2011 Apr 1;21(7):1942-7. doi: 10.1016/j.bmcl.2011.02.038. Epub 2011 Feb 15.

Structure based design, synthesis and SAR of cyclic hydroxyethylamine (HEA) BACE-1 inhibitors.

Author information

1
Novartis Institutes for BioMedical Research, Novartis Pharma AG, PO Box, CH-4002 Basel, Switzerland. heinrich.rueeger@novartis.com

Abstract

This Letter describes the de novo design of non-peptidic hydroxyethylamine (HEA) inhibitors of BACE-1 by elimination of P-gp contributing amide attachments. The predicted binding mode of the novel cyclic sulfone HEA core template was confirmed in a X-ray co-crystal structure. Inhibitors of sub-micromolar potency with an improved property profile over historic HEA inhibitors resulting in improved brain penetration are described.

PMID:
21388807
DOI:
10.1016/j.bmcl.2011.02.038
[Indexed for MEDLINE]

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