2. Academic Validation
  3. Macrocyclic BACE-1 inhibitors acutely reduce Abeta in brain after po application

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

Affiliation

  • 1 Novartis Institutes for BioMedicalResearch, Novartis Pharma AG, PO Box, CH 4002, Basel, Switzerland. andreas.lerchner@novartis.com
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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