title: (S)-N-(5-Chlorothiophene-2-sulfonyl)-beta,beta-diethylalaninol a Notch-1-sparing gamma-secretase inhibitor.
abstract: Accumulation of beta-amyloid (Abeta), produced by the proteolytic cleavage of amyloid precursor protein (APP) by beta- and gamma-secretase, is widely believed to be associated with Alzheimer's disease (AD). Research around the high-throughput screening hit (S)-4-chlorophenylsulfonyl isoleucinol led to the identification of the Notch-1-sparing (9.5-fold) gamma-secretase inhibitor (S)-N-(5-chlorothiophene-2-sulfonyl)-beta,beta-diethylalaninol 7.b.2 (Abeta(40/42) EC(50)=28 nM), which is efficacious in reduction of Abeta production in vivo.
authors.affiliation: Chemical and Screening Sciences, Wyeth Research, Pearl River, NY 10965, USA. coledc@wyeth.com
authors.forename: Derek C
authors.initials: DC
authors.lastname: Cole
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Stock
authors.forename: Anthony F
authors.initials: AF
authors.lastname: Kreft
authors.forename: Madelene
authors.initials: M
authors.lastname: Antane
authors.forename: Suzan H
authors.initials: SH
authors.lastname: Aschmies
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Atchison
authors.forename: David S
authors.initials: DS
authors.lastname: Casebier
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Comery
authors.forename: George
authors.initials: G
authors.lastname: Diamantidis
authors.forename: John W
authors.initials: JW
authors.lastname: Ellingboe
authors.forename: Boyd L
authors.initials: BL
authors.lastname: Harrison
authors.forename: Yun
authors.initials: Y
authors.lastname: Hu
authors.forename: Mei
authors.initials: M
authors.lastname: Jin
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Kubrak
authors.forename: Peimin
authors.initials: P
authors.lastname: Lu
authors.forename: Charles W
authors.initials: CW
authors.lastname: Mann
authors.forename: Robert L
authors.initials: RL
authors.lastname: Martone
authors.forename: William J
authors.initials: WJ
authors.lastname: Moore
authors.forename: Aram
authors.initials: A
authors.lastname: Oganesian
authors.forename: David R
authors.initials: DR
authors.lastname: Riddell
authors.forename: June
authors.initials: J
authors.lastname: Sonnenberg-Reines
authors.forename: Shaiu-Ching
authors.initials: SC
authors.lastname: Sun
authors.forename: Erik
authors.initials: E
authors.lastname: Wagner
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Woller
authors.forename: Zheng
authors.initials: Z
authors.lastname: Xu
authors.forename: Hua
authors.initials: H
authors.lastname: Zhou
authors.forename: J Steven
authors.initials: JS
authors.lastname: Jacobsen
mesh_terms: D000438:Alcohols; D000544:Alzheimer Disease / Q000188:drug therapy*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry; D000818:Animals; D015195:Drug Design; D006801:Humans; D007532:Isoleucine / Q000031:analogs & derivatives* / Q000737:chemistry; D008956:Models, Chemical; D011412:Propanolamines / Q000737:chemistry; D051881:Receptor, Notch1 / Q000378:metabolism*; D013449:Sulfonamides / Q000737:chemistry
chemical_list: C539992:(S)-4-chlorophenylsulfonyl isoleucinol; D000438:Alcohols; D016564:Amyloid beta-Protein Precursor; D011412:Propanolamines; D051881:Receptor, Notch1; D013449:Sulfonamides; D007532:Isoleucine; C014060:isoleucinol; C034448:2-aminopropanol; D053829:Amyloid Precursor Protein Secretases