title: The potent BACE1 inhibitor LY2886721 elicits robust central Aβ pharmacodynamic responses in mice, dogs, and humans.
abstract: BACE1 is a key protease controlling the formation of amyloid β, a peptide hypothesized to play a significant role in the pathogenesis of Alzheimer's disease (AD). Therefore, the development of potent and selective inhibitors of BACE1 has been a focus of many drug discovery efforts in academia and industry. Herein, we report the nonclinical and early clinical development of LY2886721, a BACE1 active site inhibitor that reached phase 2 clinical trials in AD. LY2886721 has high selectivity against key off-target proteases, which efficiently translates in vitro activity into robust in vivo amyloid β lowering in nonclinical animal models. Similar potent and persistent amyloid β lowering was observed in plasma and lumbar CSF when single and multiple doses of LY2886721 were administered to healthy human subjects. Collectively, these data add support for BACE1 inhibition as an effective means of amyloid lowering and as an attractive target for potential disease modification therapy in AD.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
authors.forename: Patrick C
authors.initials: PC
authors.lastname: May
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Willis
authors.affiliation: National University of Singapore Centre for Clinical Pharmacology, Singapore 117597, Singapore.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Lowe
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Dean
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Monk
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Cocke
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
authors.forename: James E
authors.identifier: http://orcid.org/0000-0003-2501-8138
authors.initials: JE
authors.lastname: Audia
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
authors.forename: Leonard N
authors.initials: LN
authors.lastname: Boggs
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Borders
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Brier
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
authors.forename: David O
authors.initials: DO
authors.lastname: Calligaro
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Day
authors.affiliation: PAREXEL International, Glendale, California 91206, and.
authors.forename: Larry
authors.initials: L
authors.lastname: Ereshefsky
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
authors.forename: Jon A
authors.initials: JA
authors.lastname: Erickson
authors.affiliation: California Clinical Trials Medical Group, Inc., Glendale, California 91206.
authors.forename: Hykop
authors.identifier: http://orcid.org/0000-0002-7096-7992
authors.initials: H
authors.lastname: Gevorkyan
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
authors.forename: Celedon R
authors.initials: CR
authors.lastname: Gonzales
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
authors.forename: Douglas E
authors.initials: DE
authors.lastname: James
authors.affiliation: PAREXEL International, Glendale, California 91206, and.
authors.forename: Stanford S
authors.initials: SS
authors.lastname: Jhee
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
authors.forename: Steven F
authors.initials: SF
authors.lastname: Komjathy
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
authors.forename: Linglin
authors.initials: L
authors.lastname: Li
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
authors.forename: Terry D
authors.initials: TD
authors.lastname: Lindstrom
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Mathes
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
authors.forename: Ferenc
authors.initials: F
authors.lastname: Martényi
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Sheehan
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Stout
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
authors.forename: David E
authors.initials: DE
authors.lastname: Timm
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
authors.forename: Grant M
authors.initials: GM
authors.lastname: Vaught
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Watson
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
authors.forename: Leonard L
authors.initials: LL
authors.lastname: Winneroski
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
authors.forename: Zhixiang
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, mergott_dustin_james@lilly.com.
authors.forename: Dustin J
authors.identifier: http://orcid.org/0000-0003-1802-0758
authors.initials: DJ
authors.lastname: Mergott
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D004195:Disease Models, Animal; D004285:Dogs; D006574:Heterocyclic Compounds, 2-Ring / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D010848:Picolinic Acids / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D011480:Protease Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D016229:Amyloid beta-Peptides; D006574:Heterocyclic Compounds, 2-Ring; C000596181:N-(3-(2-amino-4a,5,7,7a-tetrahydro-4H-furo(3,4-d)(1,3)thiazin-7a-yl)-4-fluorophenyl)-5-fluoropicolinamide; D010848:Picolinic Acids; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
keywords: Alzheimer's disease; BACE1; amyloid beta; clinical trial; nonclinical animal model