title: Design, Synthesis, and Evaluation of a Novel Series of Oxadiazine Gamma Secretase Modulators for Familial Alzheimer's Disease.
abstract: Herein we describe the design, synthesis, and evaluation of a novel series of oxadiazine-based gamma secretase modulators obtained via isosteric amide replacement and critical consideration of conformational restriction. Oxadiazine lead 47 possesses good in vitro potency with excellent predicted CNS drug-like properties and desirable ADME/PK profile. This lead compound demonstrated robust Aβ42reductions and subsequent Aβ37increases in both rodent brain and CSF at 30 mg/kg dosed orally.
authors.affiliation: FORUM Pharmaceuticals , 225 Second Avenue, Waltham, Massachusetts 02451, United States.
authors.forename: Matthew G
authors.identifier: 0000-0003-4934-7323
authors.initials: MG
authors.lastname: Bursavich
authors.forename: Bryce A
authors.initials: BA
authors.lastname: Harrison
authors.forename: Raksha
authors.initials: R
authors.lastname: Acharya
authors.forename: Donald E
authors.initials: DE
authors.lastname: Costa
authors.forename: Emily A
authors.initials: EA
authors.lastname: Freeman
authors.forename: Hilliary E
authors.initials: HE
authors.lastname: Hodgdon
authors.forename: Lori A
authors.initials: LA
authors.lastname: Hrdlicka
authors.forename: Hong
authors.initials: H
authors.lastname: Jin
authors.forename: Sudarshan
authors.initials: S
authors.lastname: Kapadnis
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Moffit
authors.forename: Deirdre A
authors.initials: DA
authors.lastname: Murphy
authors.forename: Scott
authors.initials: S
authors.lastname: Nolan
authors.forename: Holger
authors.initials: H
authors.lastname: Patzke
authors.forename: Cuyue
authors.initials: C
authors.lastname: Tang
authors.forename: Melody
authors.initials: M
authors.lastname: Wen
authors.forename: Gerhard
authors.initials: G
authors.lastname: Koenig
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Blain
authors.forename: Duane A
authors.identifier: 0000-0002-1444-7802
authors.initials: DA
authors.lastname: Burnett
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D015195:Drug Design; D006801:Humans; D008252:Macaca fascicularis; D051379:Mice; D010078:Oxazines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017208:Rats, Wistar
chemical_list: D016229:Amyloid beta-Peptides; D010078:Oxazines; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases