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Highly potent macrocyclic BACE-1 inhibitors incorporating a hydroxyethylamine core: design, synthesis and X-ray crystal structures of enzyme inhibitor complexes.
- Source :
-
Bioorganic & medicinal chemistry [Bioorg Med Chem] 2012 Jul 15; Vol. 20 (14), pp. 4377-89. Date of Electronic Publication: 2012 May 24. - Publication Year :
- 2012
-
Abstract
- A series of P1-P3 linked macrocyclic BACE-1 inhibitors containing a hydroxyethylamine (HEA) isostere scaffold has been synthesized. All inhibitors comprise a toluene or N-phenylmethanesulfonamide P2 moiety. Excellent BACE-1 potencies, both in enzymatic and cell-based assays, were observed in this series of target compounds, with the best candidates displaying cell-based IC(50) values in the low nanomolar range. As an attempt to improve potency, a phenyl substituent aiming at the S3 subpocket was introduced in the macrocyclic ring. X-ray analyzes were performed on selected compounds, and enzyme-inhibitor interactions are discussed.<br /> (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Subjects :
- Amyloid Precursor Protein Secretases metabolism
Binding Sites
Crystallography, X-Ray
Enzyme Inhibitors chemistry
Ethylamines chemical synthesis
Protein Structure, Tertiary
Structure-Activity Relationship
Amyloid Precursor Protein Secretases antagonists & inhibitors
Drug Design
Enzyme Inhibitors chemical synthesis
Ethylamines chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3391
- Volume :
- 20
- Issue :
- 14
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 22698785
- Full Text :
- https://doi.org/10.1016/j.bmc.2012.05.039