1.
Bioorg Med Chem Lett
; 20(20): 6034-9, 2010 Oct 15.
Article
in English
| MEDLINE
| ID: mdl-20822903
ABSTRACT
The structure-activity relationship of the prime region of hydroxyethylamine BACE inhibitors is described. Variation in the aryl linker region with 5- and 6-membered heterocycles provided compounds such as 33 with improved permeability and reduced P-gp liability compared to benzyl amine analog 1.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid Precursor Protein Secretases/metabolism , Aspartic Acid Endopeptidases/antagonists & inhibitors , Aspartic Acid Endopeptidases/metabolism , Ethylamines/chemistry , Ethylamines/pharmacology , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Alzheimer Disease/drug therapy , Amyloid Precursor Protein Secretases/chemistry , Aspartic Acid Endopeptidases/chemistry , Crystallography, X-Ray , Ethylamines/chemical synthesis , Humans , Models, Molecular , Protease Inhibitors/chemical synthesis , Protein Binding , Structure-Activity Relationship
2.
Bioorg Med Chem Lett
; 19(22): 6386-91, 2009 Nov 15.
Article
in English
| MEDLINE
| ID: mdl-19811916
ABSTRACT
Using structure-guided design, hydroxyethylamine BACE-1 inhibitors were optimized to nanomolar Abeta cellular inhibition with selectivity against cathepsin-D. X-ray crystallography illuminated the S1' residues critical to this effort, which culminated in compounds 56 and 57 that exhibited potency and selectivity but poor permeability and high P-gp efflux.
