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)
Full Text: HTML
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.
Related Compounds
Related Articles:
Transition metal-catalyzed synthesis and reactivity of N-alkenyl aziridines.
2005-03-17
[Org. Lett. 6th ed., 7 , 1161-1164, (2005)]
2008-01-01
[Chemistry 3rd ed., 14 , 886-894, (2008)]
2010-01-01
[Bioorg. Med. Chem. 8th ed., 18 , 2894-2901, (2010)]
Kinetic resolution of axially chiral 2,2'-dihydroxy-1,1'-biaryls by palladium-catalyzed alcoholysis.
2005-08-03
[J. Am. Chem. Soc. 30th ed., 127 , 10474-10475, (2005)]
Efforts toward distorted spiropentanes.
2010-11-05
[J. Org. Chem. 21th ed., 75 , 7494-7497, (2010)]