Aminoimidazoles as potent and selective human beta-secretase (BACE1) inhibitors.
The identification of small molecule aminoimidazoles as potent and selective human beta-secretase inhibitors is reported. These analogues demonstrate low nannomolar potency for BACE1 in a FRET assay, exhibit comparable activity in a cell-based (ELISA) assay, and show >100x selectivity for the other structurally related aspartyl proteases BACE2, cathepsin D, renin, and pepsin. Our design strategy was supported by molecular modeling studies based on the cocrystal structure of the HTS-hit 3 in the BACE1 active site. These strategies enabled us to integrate pyridine and pyrimidine groups on 3 extending deep into the S3 region of the BACE1 binding pocket and enhancing the ligand's potency. Compound (R)-37 displayed an IC50 value for BACE1 of 20 nM, cellular activity of 90 nM, and >100-fold selectivity over related aspartyl proteases. Acute oral administration of (R)-37 at 30 mg/kg resulted in a significant 71% reduction of plasma Abeta40 measured at the 6 h time point in a Tg2576 mouse model (p < 0.001).
Malamas
Michael S
MS
Department of Chemical Sciences, Wyeth Research, CN 8000, Princeton, New Jersey 08543-8000, USA. malamam@wyeth.com
Erdei
Jim
J
Gunawan
Iwan
I
Barnes
Keith
K
Johnson
Matthew
M
Hui
Yu
Y
Turner
Jim
J
Hu
Yun
Y
Wagner
Erik
E
Fan
Kristi
K
Olland
Andrea
A
Bard
Jonathan
J
Robichaud
Albert J
AJ
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D015195:Drug Design; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D010446:Peptide Fragments / Q000378:metabolism; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D016229:Amyloid beta-Peptides; D007093:Imidazoles; D008024:Ligands; D010446:Peptide Fragments; D011480:Protease Inhibitors; C078592:amyloid beta-protein (1-40); D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human