Application of Fragment-Based NMR Screening, X-ray Crystallography, Structure-Based Design, and Focused Chemical Library Design to Identify Novel [mu]M Leads for the Development of nM BACE-1 ([beta]-Site APP Cleaving Enzyme 1) Inhibitors

• Published in: Journal of medicinal chemistry Vol. 53; no. (3) ; 02, 2010
• 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: Journal Article
• Language: English
• Published: United States 18.10.2010
• Subjects: CRYSTAL STRUCTURE; CRYSTALLOGRAPHY; DESIGN; ENZYMES; FUNCTIONALS; MATERIALS SCIENCE; OPTIMIZATION; STABILITY
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm901472u

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{sub d} of 15 {micro}M 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 (J. Med. Chem. 2010, 53, DOI:10.1021/jm901408p).