Macrocyclic Inhibitors of Beta-secretase: Functional Activity in an Animal Model.
From: Department of Medicinal Chemistry, Biological Chemistry, Molecular Systems and Structural Biology Merck Research Laboratories, Post Office Box 4, West Point, Pennsylvania 19486, USA. shawn_stachel@merck.com
Journal of medicinal chemistry
- Publish Date: Oct 2006
- ISSN: 0022-2623
- Volume: 49
- Issue: 21
- Pages: 6147-50
- Medium: Print
- Language: English
- Citation (JAMA): Stachel Shawn J, Coburn Craig A, Sankaranarayanan Sethu, et al. Macrocyclic Inhibitors of Beta-secretase: Functional Activity in an Animal Model.. J. Med. Chem. Oct 2006;49:6147-50
Abstract
A macrocyclic inhibitor of beta-secretase was designed by covalently cross-linking the P1 and P3 side chains of an isophthalamide-based inhibitor. Macrocyclization resulted in significantly improved potency and physical properties when compared to the initial lead structures. More importantly, these macrocyclic inhibitors also displayed in vivo amyloid lowering when dosed in a murine model.
Mesh Headings (Keywords): Amides, Amyloid Precursor Protein Secretases, Amyloid beta-Protein, Animals, Blood-Brain Barrier, Brain, Macrocyclic Compounds, Mice, Molecular Conformation, Phthalic Acids, Protease Inhibitors, Stereoisomerism, Structure-Activity Relationship, Tissue Distribution
Check for Full Text / PubMed Unique Identifier (PMID): 17034118
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