title: Synthesis and SAR Studies of Fused Oxadiazines as γ-Secretase Modulators for Treatment of Alzheimer's Disease.
abstract: Fused oxadiazines (3) were discovered as selective and orally bioavailable γ-secretase modulators (GSMs) based on the structural framework of oxadiazoline GSMs. Although structurally related, initial modifications showed that structure-activity relationships (SARs) did not translate from the oxadiazoline to the oxadiazine series. Subsequent SAR studies on modifications at the C3 and C4 positions of the fused oxadiazine core helped to identify GSMs such as compounds 8r and 8s that were highly efficacious in vitro and in vivo in a number of animal models with highly desirable physical and pharmacological properties. Further improvements of in vitro activity and selectivity were achieved by the preparation of fused morpholine oxadiazines. The shift in specificity of APP cleavage rather than a reduction in overall γ-secretase activity and the lack of changes in substrate accumulation and Notch processing as observed in the animal studies of compound 8s confirm that the oxadiazine series of compounds are potent GSMs.
authors.affiliation: Department of Medicinal Chemistry, Department of In Vitro Biology, Department of In Vivo Biology, Drug Metabolism, and Structual Elucidation, Merck Research Laboratory , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Xianhai
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Medicinal Chemistry, Department of In Vitro Biology, Department of In Vivo Biology, Drug Metabolism, and Structual Elucidation, Merck Research Laboratory , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Department of Medicinal Chemistry, Department of In Vitro Biology, Department of In Vivo Biology, Drug Metabolism, and Structual Elucidation, Merck Research Laboratory , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Xiaoxiang
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Medicinal Chemistry, Department of In Vitro Biology, Department of In Vivo Biology, Drug Metabolism, and Structual Elucidation, Merck Research Laboratory , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Medicinal Chemistry, Department of In Vitro Biology, Department of In Vivo Biology, Drug Metabolism, and Structual Elucidation, Merck Research Laboratory , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: George
authors.initials: G
authors.lastname: Sun
authors.affiliation: Department of Medicinal Chemistry, Department of In Vitro Biology, Department of In Vivo Biology, Drug Metabolism, and Structual Elucidation, Merck Research Laboratory , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Mihirbaran
authors.initials: M
authors.lastname: Mandal
authors.affiliation: Department of Medicinal Chemistry, Department of In Vitro Biology, Department of In Vivo Biology, Drug Metabolism, and Structual Elucidation, Merck Research Laboratory , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Monica
authors.initials: M
authors.lastname: Vicarel
authors.affiliation: Department of Medicinal Chemistry, Department of In Vitro Biology, Department of In Vivo Biology, Drug Metabolism, and Structual Elucidation, Merck Research Laboratory , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Medicinal Chemistry, Department of In Vitro Biology, Department of In Vivo Biology, Drug Metabolism, and Structual Elucidation, Merck Research Laboratory , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Chad
authors.initials: C
authors.lastname: Bennett
authors.affiliation: Department of Medicinal Chemistry, Department of In Vitro Biology, Department of In Vivo Biology, Drug Metabolism, and Structual Elucidation, Merck Research Laboratory , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Troy
authors.initials: T
authors.lastname: McCraken
authors.affiliation: Department of Medicinal Chemistry, Department of In Vitro Biology, Department of In Vivo Biology, Drug Metabolism, and Structual Elucidation, Merck Research Laboratory , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Dmitri
authors.initials: D
authors.lastname: Pissarnitski
authors.affiliation: Department of Medicinal Chemistry, Department of In Vitro Biology, Department of In Vivo Biology, Drug Metabolism, and Structual Elucidation, Merck Research Laboratory , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Medicinal Chemistry, Department of In Vitro Biology, Department of In Vivo Biology, Drug Metabolism, and Structual Elucidation, Merck Research Laboratory , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: David
authors.initials: D
authors.lastname: Cole
authors.affiliation: Department of Medicinal Chemistry, Department of In Vitro Biology, Department of In Vivo Biology, Drug Metabolism, and Structual Elucidation, Merck Research Laboratory , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Gioconda
authors.initials: G
authors.lastname: Gallo
authors.affiliation: Department of Medicinal Chemistry, Department of In Vitro Biology, Department of In Vivo Biology, Drug Metabolism, and Structual Elucidation, Merck Research Laboratory , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Zhaoning
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Department of Medicinal Chemistry, Department of In Vitro Biology, Department of In Vivo Biology, Drug Metabolism, and Structual Elucidation, Merck Research Laboratory , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Anandan
authors.initials: A
authors.lastname: Palani
authors.affiliation: Department of Medicinal Chemistry, Department of In Vitro Biology, Department of In Vivo Biology, Drug Metabolism, and Structual Elucidation, Merck Research Laboratory , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Aslanian
authors.affiliation: Department of Medicinal Chemistry, Department of In Vitro Biology, Department of In Vivo Biology, Drug Metabolism, and Structual Elucidation, Merck Research Laboratory , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: John
authors.initials: J
authors.lastname: Clader
authors.affiliation: Department of Medicinal Chemistry, Department of In Vitro Biology, Department of In Vivo Biology, Drug Metabolism, and Structual Elucidation, Merck Research Laboratory , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Czarniecki
authors.affiliation: Department of Medicinal Chemistry, Department of In Vitro Biology, Department of In Vivo Biology, Drug Metabolism, and Structual Elucidation, Merck Research Laboratory , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: William
authors.initials: W
authors.lastname: Greenlee
authors.affiliation: Department of Medicinal Chemistry, Department of In Vitro Biology, Department of In Vivo Biology, Drug Metabolism, and Structual Elucidation, Merck Research Laboratory , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Duane
authors.initials: D
authors.lastname: Burnett
authors.affiliation: Department of Medicinal Chemistry, Department of In Vitro Biology, Department of In Vivo Biology, Drug Metabolism, and Structual Elucidation, Merck Research Laboratory , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Mary
authors.initials: M
authors.lastname: Cohen-Williams
authors.affiliation: Department of Medicinal Chemistry, Department of In Vitro Biology, Department of In Vivo Biology, Drug Metabolism, and Structual Elucidation, Merck Research Laboratory , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Lynn
authors.initials: L
authors.lastname: Hyde
authors.affiliation: Department of Medicinal Chemistry, Department of In Vitro Biology, Department of In Vivo Biology, Drug Metabolism, and Structual Elucidation, Merck Research Laboratory , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Lixin
authors.initials: L
authors.lastname: Song
authors.affiliation: Department of Medicinal Chemistry, Department of In Vitro Biology, Department of In Vivo Biology, Drug Metabolism, and Structual Elucidation, Merck Research Laboratory , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Lili
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Medicinal Chemistry, Department of In Vitro Biology, Department of In Vivo Biology, Drug Metabolism, and Structual Elucidation, Merck Research Laboratory , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Inhou
authors.initials: I
authors.lastname: Chu
authors.affiliation: Department of Medicinal Chemistry, Department of In Vitro Biology, Department of In Vivo Biology, Drug Metabolism, and Structual Elucidation, Merck Research Laboratory , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Alexei
authors.initials: A
authors.lastname: Buevich
keywords: Alzheimer's disease; Notch processing; amyloid precursor protein; morpholine; oxadiazine; γ-secreatase modulator