title: The discovery of fused oxadiazepines as gamma secretase modulators for treatment of Alzheimer's disease.
abstract: In an attempt to further improve overall profiles of the oxadiazine series of GSMs, in particular the hERG activity, conformational modifications of the core structure resulted in the identification of fused oxadiazepines such as 7i which had an improved hERG inhibition profile and was a highly efficacious GSM in vitro and in vivo in rats. These SAR explorations offer opportunities to identify potential drugs to treat Alzheimer's disease.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratory, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Li
authors.forename: Jun
authors.initials: J
authors.lastname: Qin
authors.forename: Pawan
authors.initials: P
authors.lastname: Dhondi
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.forename: Monica
authors.initials: M
authors.lastname: Vicarel
authors.forename: Thomas
authors.initials: T
authors.lastname: Bara
authors.forename: David
authors.initials: D
authors.lastname: Cole
authors.forename: Hubert
authors.initials: H
authors.lastname: Josien
authors.forename: Dmitri
authors.initials: D
authors.lastname: Pissarnitski
authors.forename: Zhaoning
authors.initials: Z
authors.lastname: Zhu
authors.forename: Anandan
authors.initials: A
authors.lastname: Palani
authors.forename: Robert
authors.initials: R
authors.lastname: Aslanian
authors.forename: John
authors.initials: J
authors.lastname: Clader
authors.forename: Michael
authors.initials: M
authors.lastname: Czarniecki
authors.forename: William
authors.initials: W
authors.lastname: Greenlee
authors.forename: Mary
authors.initials: M
authors.lastname: Cohen-Williams
authors.forename: Lynn
authors.initials: L
authors.lastname: Hyde
authors.forename: Lixin
authors.initials: L
authors.lastname: Song
authors.forename: Lili
authors.initials: L
authors.lastname: Zhang
authors.forename: Inhou
authors.initials: I
authors.lastname: Chu
authors.forename: Xianhai
authors.initials: X
authors.lastname: Huang
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000818:Animals; D001381:Azepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D055808:Drug Discovery; D000072237:ERG1 Potassium Channel; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D001381:Azepines; D000072237:ERG1 Potassium Channel; D004791:Enzyme Inhibitors; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D053829:Amyloid Precursor Protein Secretases