US EPA

387497 

Journal Article 

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 

Wang, YS; Strickland, C; Voigt, JH; Kennedy, ME; Beyer, BM; Senior, MM; Smith, EM; Nechuta, TL; Madison, VS; Czarniecki, M; Mckittrick, BA; Stamford, AW; Parker, EM; Hunter, JC; Greenlee, WJ; Wyss, DF 

2010 

Yes 

Journal of Medicinal Chemistry
ISSN: 0022-2623
EISSN: 1520-4804 

53 

3 

942-950 

English 

20043700 

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(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