1. Macrocyclic peptidomimetic beta-secretase (BACE-1) inhibitors with activity in vivo.
- Author
-
Machauer R, Laumen K, Veenstra S, Rondeau JM, Tintelnot-Blomley M, Betschart C, Jaton AL, Desrayaud S, Staufenbiel M, Rabe S, Paganetti P, and Neumann U
- Subjects
- Amyloid Precursor Protein Secretases chemistry, Amyloid Precursor Protein Secretases metabolism, Animals, Aspartic Acid Endopeptidases chemistry, Aspartic Acid Endopeptidases metabolism, CHO Cells, Cricetinae, Cricetulus, Crystallography, X-Ray, Humans, Macrocyclic Compounds chemistry, Macrocyclic Compounds pharmacology, Mice, Mice, Inbred C57BL, Mice, Transgenic, Peptide Fragments pharmacology, Protease Inhibitors pharmacology, Protein Structure, Secondary physiology, Amyloid Precursor Protein Secretases antagonists & inhibitors, Aspartic Acid Endopeptidases antagonists & inhibitors, Peptide Fragments chemistry, Protease Inhibitors chemistry
- 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.
- Published
- 2009
- Full Text
- View/download PDF