Bioorganic & Medicinal Chemistry Letters 2011-04-01

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

Heinrich Rueeger, Jean-Michel Rondeau, Clive McCarthy, Henrik Möbitz, Marina Tintelnot-Blomley, Ulf Neumann, Sandrine Desrayaud

Index: Bioorg. Med. Chem. Lett. 7th ed., 21 , 1942-1947, (2011)

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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.Copyright © 2011 Elsevier Ltd. All rights reserved.