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 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
Wang
Yu-Sen
YS
Schering-Plough Research Institute, 320 Bent Street, Cambridge, Massachusetts 02141, USA. allen.yu-sen.wang@spcorp.com
Strickland
Corey
C
Voigt
Johannes H
JH
Kennedy
Matthew E
ME
Beyer
Brian M
BM
Senior
Mary M
MM
Smith
Elizabeth M
EM
Nechuta
Terry L
TL
Madison
Vincent S
VS
Czarniecki
Michael
M
McKittrick
Brian A
BA
Stamford
Andrew W
AW
Parker
Eric M
EM
Hunter
John C
JC
Greenlee
William J
WJ
Wyss
Daniel F
DF
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
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