title: Discovery of a series of efficient, centrally efficacious BACE1 inhibitors through structure-based drug design.
abstract: The identification of centrally efficacious β-secretase (BACE1) inhibitors for the treatment of Alzheimer's disease (AD) has historically been thwarted by an inability to maintain alignment of potency, brain availability, and desired absorption, distribution, metabolism, and excretion (ADME) properties. In this paper, we describe a series of truncated, fused thioamidines that are efficiently selective in garnering BACE1 activity without simultaneously inhibiting the closely related cathepsin D or negatively impacting brain penetration and ADME alignment, as exemplified by 36. Upon oral administration, these inhibitors exhibit robust brain availability and are efficacious in lowering central Amyloid β (Aβ) levels in mouse and dog. In addition, chronic treatment in aged PS1/APP mice effects a decrease in the number and size of Aβ-derived plaques. Most importantly, evaluation of 36 in a 2-week exploratory toxicology study revealed no accumulation of autofluorescent material in retinal pigment epithelium or histology findings in the eye, issues observed with earlier BACE1 inhibitors.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Butler
authors.forename: Michael A
authors.initials: MA
authors.lastname: Brodney
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Beck
authors.affiliation: #Departamento de Inovação, Eurofarma Laboratorios S.A., Avenida Vereador José Diniz, 3465, Campo Belo, São Paulo, Brasil.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Barreiro
authors.forename: Charles E
authors.initials: CE
authors.lastname: Nolan
authors.forename: Feng
authors.initials: F
authors.lastname: Pan
authors.forename: Felix
authors.initials: F
authors.lastname: Vajdos
authors.forename: Kevin
authors.initials: K
authors.lastname: Parris
authors.forename: Alison H
authors.initials: AH
authors.lastname: Varghese
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Helal
authors.forename: Ricardo
authors.initials: R
authors.lastname: Lira
authors.forename: Shawn D
authors.initials: SD
authors.lastname: Doran
authors.forename: David R
authors.initials: DR
authors.lastname: Riddell
authors.forename: Leanne M
authors.initials: LM
authors.lastname: Buzon
authors.forename: Jason K
authors.initials: JK
authors.lastname: Dutra
authors.forename: Luis A
authors.initials: LA
authors.lastname: Martinez-Alsina
authors.forename: Kevin
authors.initials: K
authors.lastname: Ogilvie
authors.forename: John C
authors.initials: JC
authors.lastname: Murray
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Young
authors.forename: Kevin
authors.initials: K
authors.lastname: Atchison
authors.forename: Ashley
authors.initials: A
authors.lastname: Robshaw
authors.forename: Cathleen
authors.initials: C
authors.lastname: Gonzales
authors.affiliation: ∇WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
authors.forename: Jinlong
authors.initials: J
authors.lastname: Wang
authors.affiliation: ∇WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Brian T
authors.initials: BT
authors.lastname: O'Neill
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D000578:Amidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004285:Dogs; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D051379:Mice; D008958:Models, Molecular; D058225:Plaque, Amyloid / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000578:Amidines; D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D013438:Sulfhydryl Compounds; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human