title: 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.
abstract: 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
authors.affiliation: Schering-Plough Research Institute, 320 Bent Street, Cambridge, Massachusetts 02141, USA. allen.yu-sen.wang@spcorp.com
authors.forename: Yu-Sen
authors.initials: YS
authors.lastname: Wang
authors.forename: Corey
authors.initials: C
authors.lastname: Strickland
authors.forename: Johannes H
authors.initials: JH
authors.lastname: Voigt
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Kennedy
authors.forename: Brian M
authors.initials: BM
authors.lastname: Beyer
authors.forename: Mary M
authors.initials: MM
authors.lastname: Senior
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Smith
authors.forename: Terry L
authors.initials: TL
authors.lastname: Nechuta
authors.forename: Vincent S
authors.initials: VS
authors.lastname: Madison
authors.forename: Michael
authors.initials: M
authors.lastname: Czarniecki
authors.forename: Brian A
authors.initials: BA
authors.lastname: McKittrick
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Stamford
authors.forename: Eric M
authors.initials: EM
authors.lastname: Parker
authors.forename: John C
authors.initials: JC
authors.lastname: Hunter
authors.forename: William J
authors.initials: WJ
authors.lastname: Greenlee
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Wyss
mesh_terms: D000631:Aminopyridines / Q000737:chemistry*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D054852:Small Molecule Libraries / Q000737:chemistry*; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
chemical_list: D000631:Aminopyridines; D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C032439:alpha-aminopyridine