title: Discovery of the 3-Imino-1,2,4-thiadiazinane 1,1-Dioxide Derivative Verubecestat (MK-8931)-A β-Site Amyloid Precursor Protein Cleaving Enzyme 1 Inhibitor for the Treatment of Alzheimer's Disease.
abstract: Verubecestat 3 (MK-8931), a diaryl amide-substituted 3-imino-1,2,4-thiadiazinane 1,1-dioxide derivative, is a high-affinity β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor currently undergoing Phase 3 clinical evaluation for the treatment of mild to moderate and prodromal Alzheimer's disease. Although not selective over the closely related aspartyl protease BACE2, verubecestat has high selectivity for BACE1 over other key aspartyl proteases, notably cathepsin D, and profoundly lowers CSF and brain Aβ levels in rats and nonhuman primates and CSF Aβ levels in humans. In this annotation, we describe the discovery of 3, including design, validation, and selected SAR around the novel iminothiadiazinane dioxide core as well as aspects of its preclinical and Phase 1 clinical characterization.
authors.forename: Jack D
authors.initials: JD
authors.lastname: Scott
authors.forename: Sarah W
authors.initials: SW
authors.lastname: Li
authors.forename: Andrew P J
authors.initials: AP
authors.lastname: Brunskill
authors.forename: Xia
authors.initials: X
authors.lastname: Chen
authors.forename: Kathleen
authors.initials: K
authors.lastname: Cox
authors.forename: Jared N
authors.initials: JN
authors.lastname: Cumming
authors.forename: Mark
authors.initials: M
authors.lastname: Forman
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Gilbert
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hodgson
authors.forename: Lynn A
authors.initials: LA
authors.lastname: Hyde
authors.affiliation: Albany Molecular Research Inc. , 26 Corporate Circle, Albany, New York 12203, United States.
authors.forename: Qin
authors.initials: Q
authors.lastname: Jiang
authors.forename: Ulrich
authors.initials: U
authors.lastname: Iserloh
authors.forename: Irina
authors.initials: I
authors.lastname: Kazakevich
authors.forename: Reshma
authors.initials: R
authors.lastname: Kuvelkar
authors.forename: Hong
authors.initials: H
authors.lastname: Mei
authors.forename: John
authors.initials: J
authors.lastname: Meredith
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Misiaszek
authors.forename: Peter
authors.initials: P
authors.lastname: Orth
authors.affiliation: Albany Molecular Research Inc. , 26 Corporate Circle, Albany, New York 12203, United States.
authors.forename: Lana M
authors.initials: LM
authors.lastname: Rossiter
authors.affiliation: Albany Molecular Research Inc. , 26 Corporate Circle, Albany, New York 12203, United States.
authors.forename: Meagan
authors.initials: M
authors.lastname: Slater
authors.forename: Julie
authors.initials: J
authors.lastname: Stone
authors.forename: Corey O
authors.initials: CO
authors.lastname: Strickland
authors.forename: Johannes H
authors.initials: JH
authors.lastname: Voigt
authors.forename: Ganfeng
authors.initials: G
authors.lastname: Wang
authors.forename: Hongwu
authors.initials: H
authors.lastname: Wang
authors.forename: Yusheng
authors.initials: Y
authors.lastname: Wu
authors.forename: William J
authors.initials: WJ
authors.lastname: Greenlee
authors.forename: Eric M
authors.initials: EM
authors.lastname: Parker
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Kennedy
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Stamford
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D003499:Cyclic S-Oxides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D008252:Macaca fascicularis; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013829:Thiadiazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D016564:Amyloid beta-Protein Precursor; D003499:Cyclic S-Oxides; D013829:Thiadiazines; C000613570:verubecestat