- New flurbiprofen derivatives: Synthesis, membrane affinity and evaluation of in vitro effect on β-amyloid levels
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Alzheimer′s disease (AD) is characterized by irreversible and progressive loss of memory and cognition and profound neuronal loss. Current therapeutic strategies for the treatment of AD have been directed to a variety of targets with the aim of reversing or preventing the disease but, unfortunately, the available treatments often produce no significant clinical benefits. During the last decades compounds that inhibit or modulate γ-secretase, reducing β amyloid (Aβ) levels, have been considered as potential therapeutics for AD. Among these the (R)-enantiomer of flurbiprofen (FLU) seems to be very promising, but it shows low brain penetration. In this study, in order to improve the properties of FLU against Alzheimer′s pathogenesis we synthesized some novel FLU lipophilic analogues. Lipophilicity of the new molecules has been characterized in terms of clogP, log KC18/W and log K IAM/W values. Permeability has been determined in both gastrointestinal PAMPA (PAMPA-GI) at different pH values and in brain blood barrier PAMPA (PAMPA-BBB) models. They were also tested for their ability to inhibit in vitro γ-secretase activity using rat CTXTNA2 astrocytes. Interestingly, the investigated molecules demonstrated to reduce Aβ 42 levels without affecting the amyloid precursor protein APP level in a clear concentrations-dependent manner.
- Sozio, Piera,Marinelli, Lisa,Cacciatore, Ivana,Fontana, Antonella,Tuerkez, Hasan,Giorgioni, Gianfabio,Ambrosini, Dario,Barbato, Francesco,Grumetto, Lucia,Pacella, Stephanie,Cataldi, Amelia,Di Stefano, Antonio
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p. 10747 - 10767
(2013/10/22)
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- Atropisomeric properties of 7-, 8-, and 9-membered-ring dibenzolactams: Conformation, thermal stability, and chemical reactivity
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The atropisomeric enantiomers of 7-, 8-, and 9-membered-ring dibenzolactams were separated by using chiral HPLC, and their stereochemistries were clarified by using X-ray crystallographic analysis. The atropisomers showed high stereochemical stability with the 8-membered ring being the most stable. In 7- and 8-membered dibenzolactams, highly stereoselective C7-methylation proceeded from the lower side of the ring to provide the products with a C7-methyl group in the pseudoaxial orientation, which converted to thermodynamically more stable isomers with the pseudoequatorial C7-methyl group. In 9-membered dibenzolactam, C7-methylation occurred from the opposite (upper) side of the ring to provide a thermodynamically stable product with the pseudoequatorial C7-methyl group.
- Tabata, Hidetsugu,Suzuki, Hiroyuki,Akiba, Kumi,Takahashi, Hideyo,Natsugari, Hideaki
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experimental part
p. 5984 - 5993
(2010/11/05)
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- Synthesis of dibenzazepinones by palladium-catalyzed intramolecular arylation of o -(2′-Bromophenyl)anilide enolates
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A new approach for the convenient synthesis of dibenzazepinones is reported. The key step is the formation of the seven-membered ring through palladium-catalyzed intramolecular arylation of an anilide enolate. T'e reactions were completed in 10 min at 100 °C with moderate to excellent yields. Aminodibenzazepinone 1, the core structure in the γ-secretase inhibitor LY411575, can be prepared in five steps from 2-bromophenylboronic acid and 2-iodoaniline in 60% overall yield. The synthesis reported here compares favorably with presently available approaches to this interesting ring system.
- Pan, Xiaohong,Wilcox, Craig S.
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experimental part
p. 6445 - 6451
(2010/12/20)
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- Synthesis and axial chirality of an enantiopure aminodibenzazepinone
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A route for the synthesis of (S,S)-7-amino-5-methyl-5H-dibenzo[b,d]azepin-6(7H)-one hydrochloride is disclosed. The synthesis includes a Friedel-Crafts alkylation to form the seven-membered ring and a highly efficient classical resolution. Additional stud
- Cole, Kevin P.,Mitchell, David,Austin Carr,Stout, James R.,Belvo, Matthew D.
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scheme or table
p. 1262 - 1266
(2009/12/01)
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- CYCLOALKYL, LACTAM, LACTONE AND RELATED COMPOUNDS, PHARMACEUTICAL COMPOSITIONS COMPRISING SAME, AND METHODS FOR INHIBITING BETA-AMYLOID PEPTIDE RELEASE AND/OR ITS SYNTHESIS BY USE OF SUCH COMPOUNDS
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Disclosed are compounds which inhibit beta -amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer's disease. Also disclosed are pharmaceutical compositions comprising a compound which inhibits beta -amyloid peptide release and/or its synthesis as well as methods for treating Alzheimer's disease both prophylactically and therapeutically with such pharmaceutical compositions.
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Page/Page column 72
(2009/02/10)
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- Atropisomeric properties of the dibenzo[b,d]azepin-6-one nucleus
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(Figure Presented) Dibenzo[b,d]azepin-6-ones (2a,b) were separated by chiral HPLC into the aR- and aS-atropisomers with high stereochemical stability, and methylation at C7 of 2a stereoselectively gave the (aR*,7R*) isomer (4a), which converted to the the
- Tabata, Hidetsugu,Akiba, Kumi,Lee, Shoukou,Takahashi, Hideyo,Natsugari, Hideaki
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supporting information; experimental part
p. 4871 - 4874
(2009/05/31)
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- Novel orally active, dibenzazepinone-based γ-secretase inhibitors
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Structural modifications of the γ-secretase inhibitor, LY411575, led to a malonamide analogue (S),(S)-1 with potent inhibitory activity in vitro, but disappointing activity in a mouse model of Alzheimer's disease. Identification and replacement of a metab
- Peters, Jens-Uwe,Galley, Guido,Jacobsen, Helmut,Czech, Christian,David-Pierson, Pascale,Kitas, Eric A.,Ozmen, Laurence
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p. 5918 - 5923
(2008/09/17)
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- A multigram chemical synthesis of the γ-secretase inhibitor LY411575 and its diastereoisomers
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An improved chemical synthesis of N-2((2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N1-((7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-l-alaninamide (LY411,575, 9a), a known γ-secretase inhibitor, is described. The key synthetic steps, which
- Fauq, Abdul H.,Simpson, Katherine,Maharvi, Ghulam M.,Golde, Todd,Das, Pritam
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p. 6392 - 6395
(2008/09/16)
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- Polycyclic α-amino-ε-caprolactams and related compounds
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Disclosed are polycyclic α-amino-ε-caprolactams and related compounds which are useful as synthetic intermediates in the preparation of inhibitors of β-amyloid peptide release and/or its synthesis.
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Page/Page column 38-39
(2010/02/14)
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- Highly efficient synthesis of medium-sized lactams via intramolecular Staudinger-aza-Wittig reaction of ω-azido pentafluorophenyl ester: Synthesis and biological evaluation of LY411575 analogues
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A highly efficient method for the synthesis of medium-sized lactams based on intramolecular Staudinger-aza-Wittig reaction of ω-azido pentafluorophenyl ester has been developed. A variety of 7-10 membered lactams were synthesized in excellent yields. Appl
- Fuwa, Haruhiko,Okamura, Yumiko,Morohashi, Yuichi,Tomita, Taisuke,Iwatsubo, Takeshi,Kan, Toshiyuki,Fukuyama, Tohru,Natsugari, Hideaki
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p. 2323 - 2326
(2007/10/03)
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