Di-substituted pyridinyl aminohydantoins as potent and highly selective human beta-secretase (BACE1) inhibitors.
The identification of highly selective small molecule di-substituted pyridinyl aminohydantoins as beta-secretase inhibitors is reported. The more potent and selective analogs demonstrate low nanomolar potency for the BACE1 enzyme as measured in a FRET assay, and exhibit comparable activity in a cell-based (ELISA) assay. In addition, these pyridine-aminohydantoins are highly selectivity (>500x) against the other structurally related aspartyl proteases BACE2, cathepsin D, pepsin and renin. Our design strategy followed a traditional SAR approach and was supported by molecular modeling studies based on the previously reported aminohydantoin 3a. We have taken advantage of the amino acid difference between the BACE1 and BACE2 at the S2' pocket (BACE1 Pro(70) changed to BACE2 Lys(86)) to build ligands with >500-fold selectivity against BACE2. The addition of large substituents on the targeted ligand at the vicinity of this aberration has generated a steric conflict between the ligand and these two proteins, thus impacting the ligand's affinity and selectivity. These ligands have also shown an exceptional selectivity against cathepsin D (>5000-fold) as well as the other aspartyl proteases mentioned. One of the more potent compounds (S)-39 displayed an IC(50) value for BACE1 of 10nM, and exhibited cellular activity with an EC(50) value of 130nM in the ELISA assay.
Malamas
Michael S
MS
Department of Chemical Sciences, Wyeth Research, CN 8000, Princeton, NJ 08543-8000, USA. malamam@wyeth.com
Barnes
Keith
K
Johnson
Matthew
M
Hui
Yu
Y
Zhou
Ping
P
Turner
Jim
J
Hu
Yun
Y
Wagner
Erik
E
Fan
Kristi
K
Chopra
Rajiv
R
Olland
Andrea
A
Bard
Jonathan
J
Pangalos
Menelas
M
Reinhart
Peter
P
Robichaud
Albert J
AJ
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D018360:Crystallography, X-Ray; D006801:Humans; D006827:Hydantoins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D008970:Molecular Weight; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D006827:Hydantoins; D008024:Ligands; D011725:Pyridines; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human