Cyclic Hydroxyamidines as Amide Isosteres: Discovery of Oxadiazolines and Oxadiazines as Potent and Highly Efficacious γ-Secretase Modulators in Vivo

• Published in: Journal of medicinal chemistry 2012-01, Vol.55 (1), p.489-502
• Main Authors: Sun, Zhong-Yue, Asberom, Theodros, Bara, Thomas, Bennett, Chad, Burnett, Duane, Chu, Inhou, Clader, John, Cohen-Williams, Mary, Cole, David, Czarniecki, Michael, Durkin, James, Gallo, Gioconda, Greenlee, William, Josien, Hubert, Huang, Xianhai, Hyde, Lynn, Jones, Nicholas, Kazakevich, Irina, Li, Hongmei, Liu, Xiaoxiang, Lee, Julie, MacCoss, Malcolm, Mandal, Mihir B, McCracken, Troy, Nomeir, Amin, Mazzola, Robert, Palani, Anandan, Parker, Eric M, Pissarnitski, Dmitri A, Qin, Jun, Song, Lixin, Terracina, Giuseppe, Vicarel, Monica, Voigt, Johannes, Xu, Ruo, Zhang, Lili, Zhang, Qi, Zhao, Zhiqiang, Zhu, Xiaohong, Zhu, Zhaoning
• Format: Article
• Language: English
• Subjects: Amidines - chemical synthesis; Amidines - pharmacokinetics; Amidines - pharmacology; Amyloid beta-Peptides - metabolism; Amyloid Precursor Protein Secretases - metabolism; Animals; Brain - metabolism; Dogs; HEK293 Cells; Humans; Macaca fascicularis; Male; Oxadiazoles - chemical synthesis; Oxadiazoles - pharmacokinetics; Oxadiazoles - pharmacology; Oxazines - chemical synthesis; Oxazines - pharmacokinetics; Oxazines - pharmacology; Peptide Fragments - metabolism; Rats; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm201407j

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 Aβ42 in various animal models.