title: Cyclic hydroxyamidines as amide isosteres: discovery of oxadiazolines and oxadiazines as potent and highly efficacious γ-secretase modulators in vivo.
abstract: Cyclic hydroxyamidines were designed and validated as isosteric replacements of the amide functionality. Compounds with these structural motifs were found to be metabolically stable and to possess highly desirable pharmacokinetic profiles. These designs were applied in the identification of γ-secretase modulators leading to highly efficacious agents for reduction of central nervous system Aβ(42) in various animal models.
authors.affiliation: Department of Medicinal Chemistry, Schering Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States. ZYSUN66011@yahoo.com
authors.forename: Zhong-Yue
authors.initials: ZY
authors.lastname: Sun
authors.forename: Theodros
authors.initials: T
authors.lastname: Asberom
authors.forename: Thomas
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authors.lastname: Bara
authors.forename: Chad
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authors.lastname: Bennett
authors.forename: Duane
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authors.lastname: Burnett
authors.forename: Inhou
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authors.lastname: Chu
authors.forename: John
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authors.lastname: Clader
authors.forename: Mary
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authors.lastname: Cohen-Williams
authors.forename: David
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authors.lastname: Cole
authors.forename: Michael
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authors.lastname: Czarniecki
authors.forename: James
authors.initials: J
authors.lastname: Durkin
authors.forename: Gioconda
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authors.lastname: Gallo
authors.forename: William
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authors.lastname: Greenlee
authors.forename: Hubert
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authors.lastname: Josien
authors.forename: Xianhai
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authors.lastname: Huang
authors.forename: Lynn
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authors.lastname: Hyde
authors.forename: Nicholas
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authors.lastname: Jones
authors.forename: Irina
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authors.lastname: Kazakevich
authors.forename: Hongmei
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authors.lastname: Li
authors.forename: Xiaoxiang
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authors.lastname: Liu
authors.forename: Julie
authors.initials: J
authors.lastname: Lee
authors.forename: Malcolm
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authors.lastname: Maccoss
authors.forename: Mihir B
authors.initials: MB
authors.lastname: Mandal
authors.forename: Troy
authors.initials: T
authors.lastname: McCracken
authors.forename: Amin
authors.initials: A
authors.lastname: Nomeir
authors.forename: Robert
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authors.lastname: Mazzola
authors.forename: Anandan
authors.initials: A
authors.lastname: Palani
authors.forename: Eric M
authors.initials: EM
authors.lastname: Parker
authors.forename: Dmitri A
authors.initials: DA
authors.lastname: Pissarnitski
authors.forename: Jun
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authors.lastname: Qin
authors.forename: Lixin
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authors.lastname: Song
authors.forename: Giuseppe
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authors.lastname: Terracina
authors.forename: Monica
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authors.lastname: Vicarel
authors.forename: Johannes
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authors.lastname: Voigt
authors.forename: Ruo
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authors.lastname: Xu
authors.forename: Lili
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authors.lastname: Zhang
authors.forename: Qi
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authors.lastname: Zhang
authors.forename: Zhiqiang
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authors.lastname: Zhao
authors.forename: Xiaohong
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authors.lastname: Zhu
authors.forename: Zhaoning
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authors.lastname: Zhu
mesh_terms: D000578:Amidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D004285:Dogs; D057809:HEK293 Cells; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D010078:Oxazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000578:Amidines; D016229:Amyloid beta-Peptides; D010069:Oxadiazoles; D010078:Oxazines; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases