Application of fragment-based NMR screening, X-ray crystallography, structure-based design, and focused chemical library design to identify novel microM leads for the development of nM BACE-1 (beta-site APP cleaving enzyme 1) inhibitors

Fragment-based NMR screening, X-ray crystallography, structure-based design, and focused chemical library design were used to identify novel inhibitors for BACE-1. A rapid optimization of an initial NMR hit was achieved by a combination of NMR and a functional assay, resulting in the identification...

Full description

Saved in:
Bibliographic Details
Published in:Journal of medicinal chemistry 2010-02, Vol.53 (3), p.942-950
Main Authors: Wang, Yu-Sen, Strickland, Corey, Voigt, Johannes H, Kennedy, Matthew E, Beyer, Brian M, Senior, Mary M, Smith, Elizabeth M, Nechuta, Terry L, Madison, Vincent S, Czarniecki, Michael, McKittrick, Brian A, Stamford, Andrew W, Parker, Eric M, Hunter, John C, Greenlee, William J, Wyss, Daniel F
Format: Article
Language:English
Subjects:
Aminopyridines - chemistry
Amyloid Precursor Protein Secretases - antagonists & inhibitors
Amyloid Precursor Protein Secretases - metabolism
Aspartic Acid Endopeptidases - antagonists & inhibitors
Aspartic Acid Endopeptidases - metabolism
Crystallography, X-Ray
Drug Design
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - pharmacology
Humans
Magnetic Resonance Spectroscopy
Models, Molecular
Molecular Structure
Small Molecule Libraries - chemistry
Spectrometry, Mass, Electrospray Ionization
Structure-Activity Relationship
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Fragment-based NMR screening, X-ray crystallography, structure-based design, and focused chemical library design were used to identify novel inhibitors for BACE-1. A rapid optimization of an initial NMR hit was achieved by a combination of NMR and a functional assay, resulting in the identification of an isothiourea hit with a K(d) of 15 microM for BACE-1. NMR data and the crystal structure revealed that this hit makes H-bond interactions with the two catalytic aspartates, occupies the nonprime side region of the active site of BACE-1, and extends toward the S3 subpocket (S3sp). A focused NMR-based search for heterocyclic isothiourea isosteres resulted in several distinct classes of BACE-1 active site directed compounds with improved chemical stability and physicochemical properties. The strategy for optimization of the 2-aminopyridine lead series to potent inhibitors of BACE-1 was demonstrated. The structure-based design of a cyclic acylguanidine lead series and its optimization into nanomolar BACE-1 inhibitors are the subject of the companion paper
ISSN:1520-4804
DOI:10.1021/jm901472u