216701-21-2Relevant articles and documents
Identification and development of biphenyl substituted iminosugars as improved dual glucosylceramide synthase/neutral glucosylceramidase inhibitors
Ghisaidoobe, Amar T.,Van Den Berg, Richard J. B. H. N.,Butt, Saleem S.,Strijland, Anneke,Donker-Koopman, Wilma E.,Scheij, Saskia,Van Den Nieuwendijk, Adrianus M. C. H.,Koomen, Gerrit-Jan,Van Loevezijn, Arnold,Leemhuis, Mark,Wennekes, Tom,Van Der Stelt, Mario,Van Der Marel, Gijsbert A.,Van Boeckel, Constant A. A.,Aerts, Johannes M. F. G.,Overkleeft, Herman S.
, p. 9096 - 9104 (2015/03/14)
This work details the evaluation of a number of N-alkylated deoxynojirimycin derivatives on their merits as dual glucosylceramide synthase/neutral glucosylceramidase inhibitors. Building on our previous work, we synthesized a series of d-gluco and l-ido-configured iminosugars N-modified with a variety of hydrophobic functional groups. We found that iminosugars featuring N-pentyloxymethylaryl substituents are considerably more potent inhibitors of glucosylceramide synthase than their aliphatic counterparts. In a next optimization round, we explored a series of biphenyl-substituted iminosugars of both configurations (d-gluco and l-ido) with the aim to introduce structural features known to confer metabolic stability to drug-like molecules. From these series, two sets of molecules emerge as lead series for further profiling. Biphenyl-substituted l-ido-configured deoxynojirimycin derivatives are selective for glucosylceramidase and the nonlysosomal glucosylceramidase, and we consider these as leads for the treatment of neuropathological lysosomal storage disorders. Their d-gluco-counterparts are also potent inhibitors of intestinal glycosidases, and because of this characteristic, we regard these as the prime candidates for type 2 diabetes therapeutics.
New flurbiprofen derivatives: Synthesis, membrane affinity and evaluation of in vitro effect on β-amyloid levels
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
, p. 10747 - 10767 (2013/10/22)
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.
The superbase approach to flurbiprofen: An exercise in optionally site-selective metalation
Schlosser, Manfred,Geneste, Herve
, p. 1969 - 1973 (2007/10/03)
A superior route to the analgesic flurbiprofen has been devised. Key steps are the selective deprotonation of 3-fluorotoluene with tert-butyllithium in the presence of potassium tert-butoxide (LIT-KOR) at the 4-position and the selective deprotonation of the 4-methyl-2-fluorobiphenyl with lithium diisopropylamide in the presence of potassium tert-butoxide (LIDA-KOR) at the benzylic position. Depending on the reagent and the substituent pattern, the 3- and 5-positions of 2-fluorobiphenyls can also be specifically attacked.