title: Discovery of 2-methylpyridine-based biaryl amides as γ-secretase modulators for the treatment of Alzheimer's disease.
abstract: γ-Secretase modulators (GSMs) are potentially disease-modifying treatments for Alzheimer's disease. They selectively lower pathogenic Aβ42 levels by shifting the enzyme cleavage sites without inhibiting γ-secretase activity, possibly avoiding known adverse effects observed with complete inhibition of the enzyme complex. A cell-based HTS effort identified the sulfonamide 1 as a GSM lead. Lead optimization studies identified compound 25 with improved cell potency, PKDM properties, and it lowered Aβ42 levels in the cerebrospinal fluid (CSF) of Sprague-Dawley rats following oral administration. Further optimization of 25 to improve cellular potency is described.
authors.affiliation: Department of Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States. Electronic address: jianc@amgen.com.
authors.forename: Jian Jeffrey
authors.initials: JJ
authors.lastname: Chen
authors.forename: Wenyuan
authors.initials: W
authors.lastname: Qian
authors.forename: Kaustav
authors.initials: K
authors.lastname: Biswas
authors.forename: Chester
authors.initials: C
authors.lastname: Yuan
authors.forename: Albert
authors.initials: A
authors.lastname: Amegadzie
authors.forename: Qingyian
authors.initials: Q
authors.lastname: Liu
authors.forename: Thomas
authors.initials: T
authors.lastname: Nixey
authors.forename: Joe
authors.initials: J
authors.lastname: Zhu
authors.forename: Mqhele
authors.initials: M
authors.lastname: Ncube
authors.forename: Robert M
authors.initials: RM
authors.lastname: Rzasa
authors.forename: Frank
authors.initials: F
authors.lastname: Chavez
authors.forename: Ning
authors.initials: N
authors.lastname: Chen
authors.forename: Frenel
authors.initials: F
authors.lastname: DeMorin
authors.forename: Shannon
authors.initials: S
authors.lastname: Rumfelt
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Tegley
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Allen
authors.forename: Stephen
authors.initials: S
authors.lastname: Hitchcock
authors.forename: Randy
authors.initials: R
authors.lastname: Hungate
authors.forename: Michael D
authors.initials: MD
authors.lastname: Bartberger
authors.forename: Leeanne
authors.initials: L
authors.lastname: Zalameda
authors.forename: Yichin
authors.initials: Y
authors.lastname: Liu
authors.forename: John D
authors.initials: JD
authors.lastname: McCarter
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhang
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
authors.forename: Safura
authors.initials: S
authors.lastname: Babu-Khan
authors.forename: Yi
authors.initials: Y
authors.lastname: Luo
authors.forename: Jodi
authors.initials: J
authors.lastname: Bradley
authors.forename: Paul H
authors.initials: PH
authors.lastname: Wen
authors.forename: Darren L
authors.initials: DL
authors.lastname: Reid
authors.forename: Frank
authors.initials: F
authors.lastname: Koegler
authors.forename: Charles
authors.initials: C
authors.lastname: Dean
authors.forename: Dean
authors.initials: D
authors.lastname: Hickman
authors.forename: Tiffany L
authors.initials: TL
authors.lastname: Correll
authors.forename: Toni
authors.initials: T
authors.lastname: Williamson
authors.forename: Stephen
authors.initials: S
authors.lastname: Wood
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology; D000577:Amides / Q000737:chemistry / Q000494:pharmacology*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000818:Animals; D057809:HEK293 Cells; D006801:Humans; D010847:Picolines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000577:Amides; D010847:Picolines; C530793:2-picoline; D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer’s disease (AD); Amide as sulfonamide replacement; Amyloid β-protein (Aβ); Methylpyridine; γ-Secretase inhibitor (GSI); γ-Secretase modulator (GSM)