Macrocyclic BACE-1 inhibitors acutely reduce Abeta in brain after po application.
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.
Lerchner
Andreas
A
Novartis Institutes for BioMedicalResearch, Novartis Pharma AG, PO Box, CH 4002, Basel, Switzerland. andreas.lerchner@novartis.com
Machauer
Rainer
R
Betschart
Claudia
C
Veenstra
Siem
S
Rueeger
Heinrich
H
McCarthy
Clive
C
Tintelnot-Blomley
Marina
M
Jaton
Anne-Lise
AL
Rabe
Sabine
S
Desrayaud
Sandrine
S
Enz
Albert
A
Staufenbiel
Matthias
M
Paganetti
Paolo
P
Rondeau
Jean-Michel
JM
Neumann
Ulf
U
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D001921:Brain / Q000378:metabolism*; D002460:Cell Line; D018360:Crystallography, X-Ray; D006801:Humans; D007769:Lactams / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D047028:Macrocyclic Compounds / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016229:Amyloid beta-Peptides; D001549:Benzamides; D007769:Lactams; D047028:Macrocyclic Compounds; C548716:NB 216; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse