title: Aminomethyl-Derived Beta Secretase (BACE1) Inhibitors: Engaging Gly230 without an Anilide Functionality.
abstract: A growing subset of β-secretase (BACE1) inhibitors for the treatment of Alzheimer's disease (AD) utilizes an anilide chemotype that engages a key residue (Gly230) in the BACE1 binding site. Although the anilide moiety affords excellent potency, it simultaneously introduces a third hydrogen bond donor that limits brain availability and provides a potential metabolic site leading to the formation of an aniline, a structural motif of prospective safety concern. We report herein an alternative aminomethyl linker that delivers similar potency and improved brain penetration relative to the amide moiety. Optimization of this series identified analogues with an excellent balance of ADME properties and potency; however, potential drug-drug interactions (DDI) were predicted based on CYP 2D6 affinities. Generation and analysis of key BACE1 and CYP 2D6 crystal structures identified strategies to obviate the DDI liability, leading to compound 16, which exhibits robust in vivo efficacy as a BACE1 inhibitor.
authors.forename: Christopher R
authors.identifier: 0000-0002-9387-5011
authors.initials: CR
authors.lastname: Butler
authors.forename: Kevin
authors.initials: K
authors.lastname: Ogilvie
authors.forename: Luis
authors.initials: L
authors.lastname: Martinez-Alsina
authors.forename: Gabriela
authors.initials: G
authors.lastname: Barreiro
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Beck
authors.forename: Charles E
authors.initials: CE
authors.lastname: Nolan
authors.forename: Kevin
authors.initials: K
authors.lastname: Atchison
authors.forename: Eric
authors.initials: E
authors.lastname: Benvenuti
authors.forename: Leanne
authors.initials: L
authors.lastname: Buzon
authors.forename: Shawn
authors.initials: S
authors.lastname: Doran
authors.forename: Cathleen
authors.initials: C
authors.lastname: Gonzales
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Helal
authors.forename: Xinjun
authors.initials: X
authors.lastname: Hou
authors.affiliation: Molecular and Experimental Medicine, The Scripps Research Institute , 10550 Torrey Pines Road, La Jolla, California 92024, United States.
authors.forename: Mei-Hui
authors.initials: MH
authors.lastname: Hsu
authors.affiliation: Molecular and Experimental Medicine, The Scripps Research Institute , 10550 Torrey Pines Road, La Jolla, California 92024, United States.
authors.forename: Eric F
authors.initials: EF
authors.lastname: Johnson
authors.forename: Kimberly
authors.initials: K
authors.lastname: Lapham
authors.forename: Lorraine
authors.initials: L
authors.lastname: Lanyon
authors.forename: Kevin
authors.initials: K
authors.lastname: Parris
authors.forename: Brian T
authors.initials: BT
authors.lastname: O'Neill
authors.forename: David
authors.initials: D
authors.lastname: Riddell
authors.forename: Ashley
authors.initials: A
authors.lastname: Robshaw
authors.forename: Felix
authors.initials: F
authors.lastname: Vajdos
authors.forename: Michael A
authors.initials: MA
authors.lastname: Brodney
mesh_terms: D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000813:Anilides / Q000737:chemistry*; D000818:Animals; D001921:Brain / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003460:Crystallization; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D005998:Glycine / Q000737:chemistry*; D008297:Male; D051379:Mice; D018408:Patch-Clamp Techniques; D013329:Structure-Activity Relationship; D053719:Tandem Mass Spectrometry
chemical_list: D000813:Anilides; D004791:Enzyme Inhibitors; D053829:Amyloid Precursor Protein Secretases; D005998:Glycine