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 terms
-
Amides / chemistry
-
Amyloid Precursor Protein Secretases / metabolism*
-
Amyloid beta-Peptides / metabolism
-
Animals
-
Blood-Brain Barrier
-
Brain / metabolism
-
Macrocyclic Compounds / chemical synthesis*
-
Macrocyclic Compounds / chemistry
-
Macrocyclic Compounds / pharmacokinetics
-
Mice
-
Molecular Conformation
-
Phthalic Acids / chemistry
-
Protease Inhibitors / chemical synthesis*
-
Protease Inhibitors / chemistry
-
Protease Inhibitors / pharmacokinetics
-
Stereoisomerism
-
Structure-Activity Relationship
-
Tissue Distribution
Substances
-
Amides
-
Amyloid beta-Peptides
-
Macrocyclic Compounds
-
Phthalic Acids
-
Protease Inhibitors
-
isophthalate
-
Amyloid Precursor Protein Secretases