title: Design and synthesis of 5,5'-disubstituted aminohydantoins as potent and selective human beta-secretase (BACE1) inhibitors.
abstract: The identification of small molecule aminohydantoins as potent and selective human beta-secretase inhibitors is reported. These analogues exhibit low nannomolar potency for BACE1, show comparable activity in a cell-based (ELISA) assay, and demonstrate >100x selectivity for the other structurally related aspartyl proteases BACE2, cathepsinD, renin, and pepsin. On the basis of the cocrystal structure of the HTS-hit 2 in the BACE1 active site and by use of a structure-based drug design approach, we methodically explored the comparatively large binding pocket of the BACE1 enzyme and identified key interactions between the ligand and the protein that contributed to the affinity. One of the more potent compounds, (S)-55, displayed an IC(50) value for BACE1 of 10 nM and exhibited comparable cellular activity (EC(50) = 20 nM) in the ELISA assay. Acute oral administration of (S)-55 at 100 mg/kg resulted in a 69% reduction of plasma A beta(40) at 8 h in a Tg2576 mouse (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: 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: Rajiv
authors.initials: R
authors.lastname: Chopra
authors.forename: Andrea
authors.initials: A
authors.lastname: Olland
authors.forename: Jonathan
authors.initials: J
authors.lastname: Bard
authors.forename: Steve
authors.initials: S
authors.lastname: Jacobsen
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Magolda
authors.forename: Menelas
authors.initials: M
authors.lastname: Pangalos
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Robichaud
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D006827:Hydantoins / Q000737:chemistry*; D006860:Hydrogen Bonding; D051379:Mice; D008928:Mitochondria / Q000187:drug effects; D008956:Models, Chemical; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D006827:Hydantoins; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human