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

  • Bioorg Med Chem Lett. 2010 Jan 15;20(2):603-7. doi: 10.1016/j.bmcl.2009.11.092.
Andreas Lerchner  1 ,  Rainer Machauer ,  Claudia Betschart ,  Siem Veenstra ,  Heinrich Rueeger ,  Clive McCarthy ,  Marina Tintelnot-Blomley ,  Anne-Lise Jaton ,  Sabine Rabe ,  Sandrine Desrayaud ,  Albert Enz ,  Matthias Staufenbiel ,  Paolo Paganetti ,  Jean-Michel Rondeau ,  Ulf Neumann
Affiliations
  • 1. Novartis Institutes for BioMedicalResearch, Novartis Pharma AG, PO Box, CH 4002, Basel, Switzerland. [email protected]
PMID: 19963375 DOI: 10.1016/j.bmcl.2009.11.092
Abstract

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.

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