title: Preparation and biological evaluation of conformationally constrained BACE1 inhibitors.
abstract: The BACE1 enzyme is a key target for Alzheimer's disease. During our BACE1 research efforts, fragment screening revealed that bicyclic thiazine 3 had low millimolar activity against BACE1. Analysis of the co-crystal structure of 3 suggested that potency could be increased through extension toward the S3 pocket and through conformational constraint of the thiazine core. Pursuit of S3-binding groups produced low micromolar inhibitor 6, which informed the S3-design for constrained analogs 7 and 8, themselves prepared via independent, multi-step synthetic routes. Biological characterization of BACE inhibitors 6-8 is described.
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Leonard L
authors.initials: LL
authors.lastname: Winneroski
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Schiffler
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Jon A
authors.initials: JA
authors.lastname: Erickson
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Patrick C
authors.initials: PC
authors.lastname: May
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Monk
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Timm
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Audia
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: Beck
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Leonard N
authors.initials: LN
authors.lastname: Boggs
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Borders
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Boyer
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Brier
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Hudziak
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Valentine J
authors.initials: VJ
authors.lastname: Klimkowski
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Pablo
authors.initials: P
authors.lastname: Garcia Losada
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Mathes
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Stout
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Watson
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN 46285, USA. Electronic address: mergottdu@lilly.com.
authors.forename: Dustin J
authors.initials: DJ
authors.lastname: Mergott
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000302:isolation & purification; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000302:isolation & purification; D001923:Brain Chemistry; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D051379:Mice; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013843:Thiazines / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D001643:Bridged Bicyclo Compounds; D011480:Protease Inhibitors; D013843:Thiazines; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
keywords: BACE inhibitor; Complex organic synthesis; Conformational constraint; Stereoselective; Structure-based drug design