title: Structure activity relationship studies of tricyclic bispyran sulfone γ-secretase inhibitors.
abstract: An investigation is detailed of the structure activity relationships (SAR) of two sulfone side chains of compound (-)-1a (SCH 900229), a potent, PS1-selective γ-secretase inhibitor and clinical candidate for the treatment of Alzheimer's disease. Specifically, 4-CF(3) and 4-Br substituted arylsulfone analogs, (-)-1b and (-)-1c, are equipotent to compound (-)-1a. On the right hand side chain, linker size and terminal substituents of the pendant sulfone group are also investigated.
authors.affiliation: Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA. wen-lian.wu@merck.com
authors.forename: Wen-Lian
authors.initials: WL
authors.lastname: Wu
authors.forename: Theodros
authors.initials: T
authors.lastname: Asberom
authors.forename: Thomas
authors.initials: T
authors.lastname: Bara
authors.forename: Chad
authors.initials: C
authors.lastname: Bennett
authors.forename: Duane A
authors.initials: DA
authors.lastname: Burnett
authors.forename: John
authors.initials: J
authors.lastname: Clader
authors.forename: Martin
authors.initials: M
authors.lastname: Domalski
authors.forename: William J
authors.initials: WJ
authors.lastname: Greenlee
authors.forename: Hubert
authors.initials: H
authors.lastname: Josien
authors.forename: Mark
authors.initials: M
authors.lastname: McBriar
authors.forename: Murali
authors.initials: M
authors.lastname: Rajagopalan
authors.forename: Monica
authors.initials: M
authors.lastname: Vicarel
authors.forename: Ruo
authors.initials: R
authors.lastname: Xu
authors.forename: Lynn A
authors.initials: LA
authors.lastname: Hyde
authors.forename: Robert A
authors.initials: RA
authors.lastname: Del Vecchio
authors.forename: Mary E
authors.initials: ME
authors.lastname: Cohen-Williams
authors.forename: Lixin
authors.initials: L
authors.lastname: Song
authors.forename: Julie
authors.initials: J
authors.lastname: Lee
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Terracina
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.forename: Amin
authors.initials: A
authors.lastname: Nomeir
authors.forename: Eric M
authors.initials: EM
authors.lastname: Parker
authors.forename: Lili
authors.initials: L
authors.lastname: Zhang
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D003500:Cyclization; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D011714:Pyrans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D001578:Benzopyrans; D004791:Enzyme Inhibitors; D011714:Pyrans; C581851:SCH 900229; D013450:Sulfones; D053829:Amyloid Precursor Protein Secretases