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Macrocyclic BACE-1 Inhibitors Acutely Reduce Abeta in Brain after po Application

Lerchner, Andreas, Machauer, Rainer, Betschart, Claudia, Veenstra, Siem, Rueeger, Heinrich, Mccarthy, Clive, Tintelnot-Blomley, Marina, Jaton, Anne-Lise, Rabe, Sabine, Desrayaud, Sandrine, Enz, Albert, Staufenbiel, Matthias, Paganetti, Paolo, Rondeau, Jean-Michel and Neumann, Ulf (2009) Macrocyclic BACE-1 Inhibitors Acutely Reduce Abeta in Brain after po Application. Bioorganic and Medicinal Chemistry Letters, 20 (2). pp. 603-607. ISSN 0960-894X


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 MDCK-MDR1 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) mice after oral administration.

Item Type: Article
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Additional Information: Author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used
Keywords: Alzheimer’s disease; BACE-1 inhibitors; MDR1–MDCK; P-Glycoprotein; Reduction of Abeta in transgenic APP51/16 mice
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Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:17