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Bioorg Med Chem Lett. 2010 Jan 15;20(2):603-7. doi: 10.1016/j.bmcl.2009.11.092. Epub 2009 Nov 22.

Macrocyclic BACE-1 inhibitors acutely reduce Abeta in brain after po application.

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  • 1Novartis Institutes for BioMedicalResearch, Novartis Pharma AG, PO Box, CH 4002, Basel, Switzerland.


A series of macrocyclic peptidic BACE-1 inhibitors was designed. While potency on BACE-1 was rather high, the first set of compounds showed poor brain permeation and high efflux in the MDRI-MDCK assay. The replacement of the secondary benzylamino group with a phenylcyclopropylamino group maintained potency on BACE-1, while P-glycoprotein-mediated efflux was significantly reduced and brain permeation improved. Several compounds from this series demonstrated acute reduction of Abeta in human APP-wildtype transgenic (APP51/16) mice after oral administration.

Copyright 2009 Elsevier Ltd. All rights reserved.

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