- Structure based design, synthesis and SAR of cyclic hydroxyethylamine (HEA) BACE-1 inhibitors.
Structure based design, synthesis and SAR of cyclic hydroxyethylamine (HEA) BACE-1 inhibitors.
Bioorganic & medicinal chemistry letters (2011-03-11)
Heinrich Rueeger, Jean-Michel Rondeau, Clive McCarthy, Henrik Möbitz, Marina Tintelnot-Blomley, Ulf Neumann, Sandrine Desrayaud
PMID21388807
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.
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