title: Discovery of begacestat, a Notch-1-sparing gamma-secretase inhibitor for the treatment of Alzheimer's disease.
abstract: SAR on HTS hits 1 and 2 led to the potent, Notch-1-sparing GSI 9, which lowered brain Abeta in Tg2576 mice at 100 mg/kg po. Converting the metabolically labile methyl groups in 9 to trifluoromethyl groups afforded the more stable analogue 10, which had improved in vivo potency. Further side chain modification afforded the potent Notch-1-sparing GSI begacestat (5), which was selected for development for the treatment of Alzheimer's disease.
authors.affiliation: Chemical and Screening Sciences, and Discovery Neuroscience, Wyeth Research, CN 8000, Princeton, New Jersey 08543, USA. mayers@wyeth.com
authors.forename: Scott C
authors.initials: SC
authors.lastname: Mayer
authors.forename: Anthony F
authors.initials: AF
authors.lastname: Kreft
authors.forename: Boyd
authors.initials: B
authors.lastname: Harrison
authors.forename: Magid
authors.initials: M
authors.lastname: Abou-Gharbia
authors.forename: Madelene
authors.initials: M
authors.lastname: Antane
authors.forename: Suzan
authors.initials: S
authors.lastname: Aschmies
authors.forename: Kevin
authors.initials: K
authors.lastname: Atchison
authors.forename: Michael
authors.initials: M
authors.lastname: Chlenov
authors.forename: Derek C
authors.initials: DC
authors.lastname: Cole
authors.forename: Thomas
authors.initials: T
authors.lastname: Comery
authors.forename: George
authors.initials: G
authors.lastname: Diamantidis
authors.forename: John
authors.initials: J
authors.lastname: Ellingboe
authors.forename: Kristi
authors.initials: K
authors.lastname: Fan
authors.forename: Rocco
authors.initials: R
authors.lastname: Galante
authors.forename: Cathleen
authors.initials: C
authors.lastname: Gonzales
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Ho
authors.forename: Molly E
authors.initials: ME
authors.lastname: Hoke
authors.forename: Yun
authors.initials: Y
authors.lastname: Hu
authors.forename: Donna
authors.initials: D
authors.lastname: Huryn
authors.forename: Uday
authors.initials: U
authors.lastname: Jain
authors.forename: Mei
authors.initials: M
authors.lastname: Jin
authors.forename: Kenneth
authors.initials: K
authors.lastname: Kremer
authors.forename: Dennis
authors.initials: D
authors.lastname: Kubrak
authors.forename: Melissa
authors.initials: M
authors.lastname: Lin
authors.forename: Peimin
authors.initials: P
authors.lastname: Lu
authors.forename: Ron
authors.initials: R
authors.lastname: Magolda
authors.forename: Robert
authors.initials: R
authors.lastname: Martone
authors.forename: William
authors.initials: W
authors.lastname: Moore
authors.forename: Aram
authors.initials: A
authors.lastname: Oganesian
authors.forename: Menelas N
authors.initials: MN
authors.lastname: Pangalos
authors.forename: Alex
authors.initials: A
authors.lastname: Porte
authors.forename: Peter
authors.initials: P
authors.lastname: Reinhart
authors.forename: Lynn
authors.initials: L
authors.lastname: Resnick
authors.forename: David R
authors.initials: DR
authors.lastname: Riddell
authors.forename: June
authors.initials: J
authors.lastname: Sonnenberg-Reines
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Stock
authors.forename: Shaiu-Ching
authors.initials: SC
authors.lastname: Sun
authors.forename: Erik
authors.initials: E
authors.lastname: Wagner
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.forename: Kevin
authors.initials: K
authors.lastname: Woller
authors.forename: Zheng
authors.initials: Z
authors.lastname: Xu
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Zaleska
authors.forename: Joseph
authors.initials: J
authors.lastname: Zeldis
authors.forename: Minsheng
authors.initials: M
authors.lastname: Zhang
authors.forename: Hua
authors.initials: H
authors.lastname: Zhou
authors.forename: J Steven
authors.initials: JS
authors.lastname: Jacobsen
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D008968:Molecular Conformation; D051881:Receptor, Notch1 / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D051881:Receptor, Notch1; D013449:Sulfonamides; D013876:Thiophenes; C539549:begacestat; D053829:Amyloid Precursor Protein Secretases