title: New aminoimidazoles as β-secretase (BACE-1) inhibitors showing amyloid-β (Aβ) lowering in brain.
abstract: Amino-2H-imidazoles are described as a new class of BACE-1 inhibitors for the treatment of Alzheimer's disease. Synthetic methods, crystal structures, and structure-activity relationships for target activity, permeability, and hERG activity are reported and discussed. Compound (S)-1m was one of the most promising compounds in this report, with high potency in the cellular assay and a good overall profile. When guinea pigs were treated with compound (S)-1m, a concentration and time dependent decrease in Aβ40 and Aβ42 levels in plasma, brain, and CSF was observed. The maximum reduction of brain Aβ was 40-50%, 1.5 h after oral dosing (100 μmol/kg). The results presented highlight the potential of this new class of BACE-1 inhibitors with good target potency and with low effect on hERG, in combination with a fair CNS exposure in vivo.
authors.affiliation: Department of Medicinal Chemistry, AstraZeneca R&D Södertälje, SE-151 85 Södertälje, Sweden. ylva.gravenfors@hotmail.com
authors.forename: Ylva
authors.initials: Y
authors.lastname: Gravenfors
authors.forename: Jenny
authors.initials: J
authors.lastname: Viklund
authors.forename: Jan
authors.initials: J
authors.lastname: Blid
authors.forename: Tobias
authors.initials: T
authors.lastname: Ginman
authors.forename: Sofia
authors.initials: S
authors.lastname: Karlström
authors.forename: Jacob
authors.initials: J
authors.lastname: Kihlström
authors.forename: Karin
authors.initials: K
authors.lastname: Kolmodin
authors.forename: Johan
authors.initials: J
authors.lastname: Lindström
authors.forename: Stefan
authors.initials: S
authors.lastname: von Berg
authors.forename: Fredrik
authors.initials: F
authors.lastname: von Kieseritzky
authors.forename: Krisztian
authors.initials: K
authors.lastname: Bogar
authors.forename: Can
authors.initials: C
authors.lastname: Slivo
authors.forename: Britt-Marie
authors.initials: BM
authors.lastname: Swahn
authors.forename: Lise-Lotte
authors.initials: LL
authors.lastname: Olsson
authors.forename: Patrik
authors.initials: P
authors.lastname: Johansson
authors.forename: Susanna
authors.initials: S
authors.lastname: Eketjäll
authors.forename: Johanna
authors.initials: J
authors.lastname: Fälting
authors.forename: Fredrik
authors.initials: F
authors.lastname: Jeppsson
authors.forename: Kia
authors.initials: K
authors.lastname: Strömberg
authors.forename: Juliette
authors.initials: J
authors.lastname: Janson
authors.forename: Fredrik
authors.initials: F
authors.lastname: Rahm
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D016229:Amyloid beta-Peptides / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002460:Cell Line; D018360:Crystallography, X-Ray; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D015394:Molecular Structure; D010446:Peptide Fragments / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism*; D010539:Permeability; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D016229:Amyloid beta-Peptides; D007093:Imidazoles; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human