title: Aminoimidazoles as potent and selective human beta-secretase (BACE1) inhibitors.
abstract: 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).
authors.affiliation: Department of Chemical Sciences, Wyeth Research, CN 8000, Princeton, New Jersey 08543-8000, USA. malamam@wyeth.com
authors.forename: Michael S
authors.initials: MS
authors.lastname: Malamas
authors.forename: Jim
authors.initials: J
authors.lastname: Erdei
authors.forename: Iwan
authors.initials: I
authors.lastname: Gunawan
authors.forename: Keith
authors.initials: K
authors.lastname: Barnes
authors.forename: Matthew
authors.initials: M
authors.lastname: Johnson
authors.forename: Yu
authors.initials: Y
authors.lastname: Hui
authors.forename: Jim
authors.initials: J
authors.lastname: Turner
authors.forename: Yun
authors.initials: Y
authors.lastname: Hu
authors.forename: Erik
authors.initials: E
authors.lastname: Wagner
authors.forename: Kristi
authors.initials: K
authors.lastname: Fan
authors.forename: Andrea
authors.initials: A
authors.lastname: Olland
authors.forename: Jonathan
authors.initials: J
authors.lastname: Bard
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Robichaud
mesh_terms: 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
chemical_list: 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