Abstract
Based on a lead compound identified from the patent literature, we developed patentably novel BACE-1 inhibitors by introducing a cyclic amine scaffold as embodied by 1a and 1b. Extensive SAR studies assessed a variety of isophthalamide replacements including substituted pyrrolidinones and ultimately led to the identification of 11. Due to its favorable overall profile, 11 has been extensively profiled in various in vivo settings.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
-
Administration, Oral
-
Amides / chemistry
-
Amides / pharmacokinetics
-
Amides / pharmacology
-
Amyloid Precursor Protein Secretases / antagonists & inhibitors*
-
Amyloid Precursor Protein Secretases / chemistry
-
Amyloid Precursor Protein Secretases / metabolism
-
Animals
-
Aspartic Acid Endopeptidases / antagonists & inhibitors*
-
Aspartic Acid Endopeptidases / chemistry
-
Aspartic Acid Endopeptidases / metabolism
-
Crystallography, X-Ray
-
Humans
-
Hydrogen Bonding
-
Mice
-
Mice, Transgenic
-
Models, Molecular
-
Phenols / chemistry
-
Protease Inhibitors / chemistry*
-
Protease Inhibitors / pharmacokinetics*
-
Protease Inhibitors / pharmacology
-
Pyrrolidines / chemistry*
-
Pyrrolidines / pharmacokinetics*
-
Pyrrolidines / pharmacology
-
Rats
-
Structure-Activity Relationship
Substances
-
Amides
-
Phenols
-
Protease Inhibitors
-
Pyrrolidines
-
phenoxy radical
-
Amyloid Precursor Protein Secretases
-
Aspartic Acid Endopeptidases
-
BACE1 protein, human
-
Bace1 protein, mouse
Associated data
-
PDB/2QMD
-
PDB/2QMF
-
PDB/2QMG