Design and Synthesis of 5,5′-Disubstituted Aminohydantoins as Potent and Selective Human β-Secretase (BACE1) Inhibitors

• Published in: Journal of medicinal chemistry Vol. 53; no. 3; pp. 1146 - 1158
• Main Authors: Malamas, Michael S, Erdei, Jim, Gunawan, Iwan, Turner, Jim, Hu, Yun, Wagner, Erik, Fan, Kristi, Chopra, Rajiv, Olland, Andrea, Bard, Jonathan, Jacobsen, Steve, Magolda, Ronald L, Pangalos, Menelas, Robichaud, Albert J
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 11.02.2010; Amer Chemical Soc
• Subjects: Amyloid Precursor Protein Secretases - antagonists & inhibitors; Animals; Aspartic Acid Endopeptidases - antagonists & inhibitors; Biological and medical sciences; Chemistry, Medicinal; CHO Cells; Cricetinae; Cricetulus; Crystallography, X-Ray; Drug Design; Humans; Hydantoins - chemistry; Hydrogen Bonding; Life Sciences & Biomedicine; Medical sciences; Mice; Mitochondria - drug effects; Models, Chemical; Molecular Structure; Neuropharmacology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Protease Inhibitors - chemical synthesis; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Science & Technology; Structure-Activity Relationship; SITE; CROSS-COUPLING REACTIONS; HYDROXY ETHYLAMINES HEAS; X-RAY CRYSTALLOGRAPHY; NANOMOLAR POTENCY; ALZHEIMERS-DISEASE; AMYLOID PRECURSOR PROTEIN; IDENTIFICATION; DISCOVERY; 2ND-GENERATION; Molecular structure; Binding site; Selectivity; Modeling; Molecular model; β-secretase; Aspartic endopeptidases; Chemical synthesis; Human; Enzyme; Rodentia; Enzyme inhibitor; Antialzheimer agent; X ray diffraction; Hydantoins; In vitro; Biological activity; Amyloid precursor protein; Peptidases; In vivo; Vertebrata; Mammalia; Mouse; β Amyloid protein; Animal; Hydrolases; S configuration; Crystalline structure
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm901414e

The identification of small molecule aminohydantoins as potent and selective human β-secretase inhibitors is reported. These analogues exhibit low nannomolar potency for BACE1, show comparable activity in a cell-based (ELISA) assay, and demonstrate >100× 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 IC50 value for BACE1 of 10 nM and exhibited comparable cellular activity (EC50 = 20 nM) in the ELISA assay. Acute oral administration of (S)-55 at 100 mg/kg resulted in a 69% reduction of plasma Aβ40 at 8 h in a Tg2576 mouse (p < 0.001).