title: Macrocyclic peptidomimetic beta-secretase (BACE-1) inhibitors with activity in vivo.
abstract: The macrocyclic peptidic BACE-1 inhibitors 2a-c show moderate enzymatic and cellular activity. By exchange of the hydroxyethylene- to ethanolamine-transition state mimetic the peptidic character was reduced, providing the highly potent and selective inhibitor 3. Variation of the P' moiety resulted in the macrocyclic inhibitor 14. Both macrocycles show inhibition of BACE-1 in the brain of APP51/16 transgenic mice, 3 (NB-544) after intravenous and 14 (NB-533) after oral application.
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, PO Box, CH-4002 Basel, Switzerland.
authors.forename: Rainer
authors.initials: R
authors.lastname: Machauer
authors.forename: Kurt
authors.initials: K
authors.lastname: Laumen
authors.forename: Siem
authors.initials: S
authors.lastname: Veenstra
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Rondeau
authors.forename: Marina
authors.initials: M
authors.lastname: Tintelnot-Blomley
authors.forename: Claudia
authors.initials: C
authors.lastname: Betschart
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Jaton
authors.forename: Sandrine
authors.initials: S
authors.lastname: Desrayaud
authors.forename: Matthias
authors.initials: M
authors.lastname: Staufenbiel
authors.forename: Sabine
authors.initials: S
authors.lastname: Rabe
authors.forename: Paolo
authors.initials: P
authors.lastname: Paganetti
authors.forename: Ulf
authors.initials: U
authors.lastname: Neumann
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D006801:Humans; D047028:Macrocyclic Compounds / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000737:chemistry* / Q000494:pharmacology; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D017433:Protein Structure, Secondary / Q000502:physiology
chemical_list: D047028:Macrocyclic Compounds; D010446:Peptide Fragments; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human