title: Inhibitors of β-site amyloid precursor protein cleaving enzyme (BACE1): identification of (S)-7-(2-fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5'H-spiro[chromeno[2,3-b]pyridine-5,4'-oxazol]-2'-amine (AMG-8718).
abstract: We have previously shown that the aminooxazoline xanthene scaffold can generate potent and orally efficacious BACE1 inhibitors although certain of these compounds exhibited potential hERG liabilities. In this article, we describe 4-aza substitution on the xanthene core as a means to increase BACE1 potency while reducing hERG binding affinity. Further optimization of the P3 and P2' side chains resulted in the identification of 42 (AMG-8718), a compound with a balanced profile of BACE1 potency, hERG binding affinity, and Pgp recognition. This compound produced robust and sustained reductions of CSF and brain Aβ levels in a rat pharmacodynamic model and exhibited significantly reduced potential for QTc elongation in a cardiovascular safety model.
authors.affiliation: Departments of Therapeutic Discovery, ‡Neuroscience, §Molecular Structure and Characterization, ∥Pharmacokinetics and Drug Metabolism, and ⊥Comparative Biology and Safety Sciences, Amgen, Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Dineen
authors.forename: Kui
authors.initials: K
authors.lastname: Chen
authors.forename: Alan C
authors.initials: AC
authors.lastname: Cheng
authors.forename: Katayoun
authors.initials: K
authors.lastname: Derakhchan
authors.forename: Oleg
authors.initials: O
authors.lastname: Epstein
authors.forename: Joel
authors.initials: J
authors.lastname: Esmay
authors.forename: Dean
authors.initials: D
authors.lastname: Hickman
authors.forename: Chuck E
authors.initials: CE
authors.lastname: Kreiman
authors.forename: Isaac E
authors.initials: IE
authors.lastname: Marx
authors.forename: Robert C
authors.initials: RC
authors.lastname: Wahl
authors.forename: Paul H
authors.initials: PH
authors.lastname: Wen
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Weiss
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Whittington
authors.forename: Stephen
authors.initials: S
authors.lastname: Wood
authors.forename: Robert T
authors.initials: RT
authors.lastname: Fremeau
authors.forename: Ryan D
authors.initials: RD
authors.lastname: White
authors.forename: Vinod F
authors.initials: VF
authors.lastname: Patel
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000494:pharmacology; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008862:Microsomes, Liver / Q000378:metabolism; D011480:Protease Inhibitors / Q000138:chemical synthesis*; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: C000595381:(S)-7-(2-fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5'H-spiro(chromeno(2,3-b)pyridine-5,4'-oxazol)-2'-amine; D016229:Amyloid beta-Peptides; D001578:Benzopyrans; D051638:Ether-A-Go-Go Potassium Channels; C496884:KCNH1 protein, human; D011480:Protease Inhibitors; D011725:Pyridines; D013141:Spiro Compounds; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human