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.
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Cyclic hydroxyamidines as amide isosteres: discovery of oxadiazolines and oxadiazines as potent and highly efficacious γ-secretase modulators in vivo.
J Med Chem
January 2012
Department of Medicinal Chemistry, Schering Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
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.
View Article and Find Full Text PDFDesign and synthesis of amidine-type peptide bond isosteres: application of nitrile oxide derivatives as active ester equivalents in peptide and peptidomimetics synthesis.
Org Biomol Chem
May 2011
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan.
Amidine-type peptide bond isosteres were designed based on the substitution of the peptide bond carbonyl (C=O) group with an imino (C=NH) group. The positively-charged property of the isosteric part resembles a reduced amide-type peptidomimetic. The peptidyl amidine units were synthesized by the reduction of a key amidoxime (N-hydroxyamidine) precursor, which was prepared from nitrile oxide components as an aminoacyl or peptidyl equivalent.
View Article and Find Full Text PDFN,N-Bis-(2,6-di-methyl-phen-yl)-N-hydroxyformamidine N,N'-bis-(2,6-dimethyl-phen-yl)-N-oxidoformamidinium dichloro-methane solvate.
Acta Crystallogr Sect E Struct Rep Online
September 2009
Département de Chimie, Université de Montréal, CP 6128, Succ. Centre-ville, Montréal, Québec, Canada H3C 3J7.
The title compound, 2C(17)H(20)N(2)O·CH(2)Cl(2), was obtained by N-oxidation of the parent formamidine with m-chloro-peroxy-benzoic acid (m-CPBA). This is the first use of the above-mentioned synthetic route for the preparation of hydroxy-amidines. The title compound crystallizes as a cyclic dimer resulting from the presence of O-H⋯O and N-H⋯N hydrogen bonds.
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