title: Design and synthesis of β-site amyloid precursor protein cleaving enzyme (BACE1) inhibitors with in vivo brain reduction of β-amyloid peptides.
abstract: The evaluation of a series of aminoisoindoles as β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors and the discovery of a clinical candidate drug for Alzheimer's disease, (S)-32 (AZD3839), are described. The improvement in permeability properties by the introduction of fluorine adjacent to the amidine moiety, resulting in in vivo brain reduction of Aβ40, is discussed. Due to the basic nature of these compounds, they displayed affinity for the human ether-a-go-go related gene (hERG) ion channel. Different ways to reduce hERG inhibition and increase hERG margins for this series are described, culminating in (S)-16 and (R)-41 showing large in vitro margins with BACE1 cell IC(50) values of 8.6 and 0.16 nM, respectively, and hERG IC(50) values of 16 and 2.8 μM, respectively. Several compounds were advanced into pharmacodynamic studies and demonstrated significant reduction of β-amyloid peptides in mouse brain following oral dosing.
authors.affiliation: Department of Medicinal Chemistry, AstraZeneca R&D Södertälje, SE-151 85, Södertälje, Sweden. brittmarieswahn@gmail.com
authors.forename: Britt-Marie
authors.initials: BM
authors.lastname: Swahn
authors.forename: Karin
authors.initials: K
authors.lastname: Kolmodin
authors.forename: Sofia
authors.initials: S
authors.lastname: Karlström
authors.forename: Stefan
authors.initials: S
authors.lastname: von Berg
authors.forename: Peter
authors.initials: P
authors.lastname: Söderman
authors.forename: Jörg
authors.initials: J
authors.lastname: Holenz
authors.forename: Stefan
authors.initials: S
authors.lastname: Berg
authors.forename: Johan
authors.initials: J
authors.lastname: Lindström
authors.forename: Marie
authors.initials: M
authors.lastname: Sundström
authors.forename: Dominika
authors.initials: D
authors.lastname: Turek
authors.forename: Jacob
authors.initials: J
authors.lastname: Kihlström
authors.forename: Can
authors.initials: C
authors.lastname: Slivo
authors.forename: Lars
authors.initials: L
authors.lastname: Andersson
authors.forename: David
authors.initials: D
authors.lastname: Pyring
authors.forename: Didier
authors.initials: D
authors.lastname: Rotticci
authors.forename: Liselotte
authors.initials: L
authors.lastname: Ohberg
authors.forename: Annika
authors.initials: A
authors.lastname: Kers
authors.forename: Krisztian
authors.initials: K
authors.lastname: Bogar
authors.forename: Fredrik
authors.initials: F
authors.lastname: von Kieseritzky
authors.forename: Margareta
authors.initials: M
authors.lastname: Bergh
authors.forename: Lise-Lotte
authors.initials: LL
authors.lastname: Olsson
authors.forename: Juliette
authors.initials: J
authors.lastname: Janson
authors.forename: Susanna
authors.initials: S
authors.lastname: Eketjäll
authors.forename: Biljana
authors.initials: B
authors.lastname: Georgievska
authors.forename: Fredrik
authors.initials: F
authors.lastname: Jeppsson
authors.forename: Johanna
authors.initials: J
authors.lastname: Fälting
mesh_terms: D000284:Administration, Oral; D000480:Alkynes / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D000577:Amides / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; 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; D001682:Biological Availability; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D018360:Crystallography, X-Ray; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D005260:Female; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D006860:Hydrogen Bonding; D007211:Indoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D015394:Molecular Structure; D010446:Peptide Fragments / Q000378:metabolism; D010539:Permeability; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C578092:AZD3839; D000480:Alkynes; D000577:Amides; D016229:Amyloid beta-Peptides; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D007211:Indoles; C000606913:KCNH2 protein, human; D010446:Peptide Fragments; D011743:Pyrimidines; C078592:amyloid beta-protein (1-40); D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human