Abstract
A novel class of pyridinyl aminohydantoins was designed and prepared as highly potent BACE1 inhibitors. Compound (S)-4g showed excellent potency with IC(50) of 20 nM for BACE1. X-ray crystallography indicated that the interaction between pyridine nitrogen and the tryptophan Trp76 was a key feature in the S2' region of the enzyme that contributed to increased potency.
2010 Elsevier Ltd. All rights reserved.
MeSH terms
-
Alzheimer Disease / drug therapy*
-
Amyloid Precursor Protein Secretases / antagonists & inhibitors*
-
Amyloid Precursor Protein Secretases / chemistry
-
Amyloid Precursor Protein Secretases / metabolism*
-
Aspartic Acid Endopeptidases / antagonists & inhibitors*
-
Aspartic Acid Endopeptidases / chemistry
-
Aspartic Acid Endopeptidases / metabolism*
-
Crystallography, X-Ray
-
Humans
-
Hydantoins / chemistry
-
Hydantoins / pharmacology*
-
Models, Molecular
-
Protein Binding
-
Pyridines / chemistry
-
Pyridines / pharmacology*
-
Structure-Activity Relationship
Substances
-
Hydantoins
-
Pyridines
-
Amyloid Precursor Protein Secretases
-
Aspartic Acid Endopeptidases
-
BACE1 protein, human