title: Discovery of an Orally Available, Brain Penetrant BACE1 Inhibitor that Affords Robust CNS Aβ Reduction.
abstract: Inhibition of BACE1 to prevent brain Aβ peptide formation is a potential disease-modifying approach to the treatment of Alzheimer's disease. Despite over a decade of drug discovery efforts, the identification of brain-penetrant BACE1 inhibitors that substantially lower CNS Aβ levels following systemic administration remains challenging. In this report we describe structure-based optimization of a series of brain-penetrant BACE1 inhibitors derived from an iminopyrimidinone scaffold. Application of structure-based design in tandem with control of physicochemical properties culminated in the discovery of compound 16, which potently reduced cortex and CSF Aβ40 levels when administered orally to rats.
authors: Department of Medicinal Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors: Andrew W
authors: AW
authors: Stamford
authors: Jack D
authors: JD
authors: Scott
authors: Sarah W
authors: SW
authors: Li
authors: Suresh
authors: S
authors: Babu
authors: Dawit
authors: D
authors: Tadesse
authors: Rachael
authors: R
authors: Hunter
authors: Yusheng
authors: Y
authors: Wu
authors: Jeffrey
authors: J
authors: Misiaszek
authors: Jared N
authors: JN
authors: Cumming
authors: Eric J
authors: EJ
authors: Gilbert
authors: Chunli
authors: C
authors: Huang
authors: Brian A
authors: BA
authors: McKittrick
authors: Liwu
authors: L
authors: Hong
authors: Tao
authors: T
authors: Guo
authors: Zhaoning
authors: Z
authors: Zhu
authors: Corey
authors: C
authors: Strickland
authors: Peter
authors: P
authors: Orth
authors: Johannes H
authors: JH
authors: Voigt
authors: Matthew E
authors: ME
authors: Kennedy
authors: Xia
authors: X
authors: Chen
authors: Reshma
authors: R
authors: Kuvelkar
authors: Robert
authors: R
authors: Hodgson
authors: Lynn A
authors: LA
authors: Hyde
authors: Kathleen
authors: K
authors: Cox
authors: Leonard
authors: L
authors: Favreau
authors: Eric M
authors: EM
authors: Parker
authors: William J
authors: WJ
authors: Greenlee
keywords: Alzheimer’s disease; Aβ40; BACE1; X-ray crystallography; iminopyrimidinone; inhibitor