Cikos A.,Fidelta Ltd. |
Triballeau N.,Galapagos SASU |
Hubbard P.A.,BioFocus DPI Ltd. |
Hubbard P.A.,Cedars Sinai Medical Center |
And 7 more authors.
Organic Letters | Year: 2016
A conformational study of branimycin was performed using single-crystal X-ray crystallography to characterize the solid-state form, while a combination of NMR spectroscopy and molecular modeling was employed to gain information about the solution structure. Comparison of the crystal structure with its solution counterpart showed no significant differences in conformation, confirming the relative rigidity of the tricyclic system. However, these experiments revealed that the formerly proposed stereochemistry of branimycin at 17-C should be revised. (Chemical Equation Presented). © 2016 American Chemical Society.
PubMed | University of Namur, BioFocus DPI Ltd., Fidelta Ltd., Galapagos and Galapagos SASU
Type: Journal Article | Journal: Organic letters | Year: 2016
A conformational study of branimycin was performed using single-crystal X-ray crystallography to characterize the solid-state form, while a combination of NMR spectroscopy and molecular modeling was employed to gain information about the solution structure. Comparison of the crystal structure with its solution counterpart showed no significant differences in conformation, confirming the relative rigidity of the tricyclic system. However, these experiments revealed that the formerly proposed stereochemistry of branimycin at 17-C should be revised.
Commare B.,University of Paris Descartes |
Commare B.,CNRS Molecular Chemistry Laboratory |
Rigault D.,University of Paris Descartes |
Lemasson I.A.,University of Paris Descartes |
And 13 more authors.
Organic and Biomolecular Chemistry | Year: 2015
A series of phosphinic glutamate derivatives (e.g.LSP1-2111) have been proven to be potent agonists of metabotropic glutamate (mGlu) receptors and shown promising in vivo activity. However, so far all were synthesized and tested as a mixture of two diastereomers whose absolute and relative configurations are not known. In this study, the stereomers were separated on a Crownpack CR(+) column and their absolute configuration was assessed by means of a diastereoselective synthesis. Both separated l-stereomers activated the mGlu4 receptor with EC50's of 0.72 and 4.4 μM for (1S,1′S)-and (1S,1′R)-LSP1-2111, respectively. This journal is © The Royal Society of Chemistry.
Vodicka P.,Harvard University |
Lim J.,Mount Sinai School of Medicine |
Williams D.T.,Harvard University |
Kegel K.B.,Harvard University |
And 13 more authors.
Journal of Huntington's disease | Year: 2014
Increasing mutant huntingtin (mHTT) clearance through the autophagy pathway may be a way to treat Huntington's disease (HD). Tools to manipulate and measure autophagy flux in brain in vivo are not well established. To examine the in vivo pharmacokinetics and pharmacodynamics of the lysosomal inhibitor chloroquine (CQ) and the levels of selected autophagy markers to determine usefulness of CQ as a tool to study autophagy flux in brain. Intraperitoneal injections of CQ were administered to WT and HD(Q175/Q175) mice. CQ levels were measured by LC-MS/MS in WT brain, muscle and blood at 4 to 24 hours after the last dose. Two methods of tissue preparation were used to detect by Western blot levels of the macroautophagy markers LC3 II and p62, the chaperone mediated autophagy receptor LAMP-2A and the late endosome/lysosomal marker RAB7. Following peripheral administration, CQ levels were highest in muscle and declined rapidly between 4 and 24 hours. In the brain, CQ levels were greater in the cortex than striatum, and levels persisted up to 24 hours post-injection. CQ treatment induced changes in LC3 II and p62 that were variable across regions and tissue preparations. HD(Q175/Q175) mice exposed to CQ had variable but diminished levels of LC3 II, p62 and LAMP-2A, and increased levels of RAB7. Higher levels of mHTT were found in the membrane compartment of CQ treated HD mice. Our findings suggest that the response of brain to CQ treatment, a blocker of autophagy flux, is variable and not as robust as it has been demonstrated in vitro, suggesting that CQ treatment has limitations for modulating autophagy flux in vivo. Alternative methods, compounds, and technologies need to be developed to further investigate autophagy flux in vivo, especially in the brain.
Bard J.,CHDI Foundation |
Wall M.D.,BioFocus DPI Ltd |
Lazari O.,BioFocus DPI Ltd |
Arjomand J.,CHDI Foundation |
Munoz-Sanjuan I.,CHDI Foundation
Journal of Biomolecular Screening | Year: 2014
Huntington disease is a monogenic, autosomal dominant, progressive neurodegenerative disorder caused by a trinucleotide CAG repeat expansion in exon 1 of the huntingtin (HTT) gene; age of onset of clinical symptoms inversely correlates with expanded CAG repeat length. HD leads to extensive degeneration of the basal ganglia, hypothalamic nuclei, and selected cortical areas, and a wide range of molecular mechanisms have been implicated in disease pathology in animal or cellular models expressing mutated HTT (mHTT) proteins, either full-length or amino-terminal fragments. However, HD cellular models that recapitulate the slow progression of the disease have not been available due to the toxicity of overexpressed exogenous mHTT or to limitations with using primary cells for long-term studies. Most investigations of the effects of mHTT relied on cytotoxicity or aggregation end points in heterologous systems or in primary embryonic neuroglial cultures derived from HD mouse models. More innovative approaches are currently under active investigation, including screening using electrophysiological endpoints, as well as the recent use of primary blood mononuclear cells and of human embryonic stem cells derived from a variety of HD research participants. Here we describe how these cellular systems are being used to investigate HD biology as well as to identify mechanisms with therapeutic potential. © 2013 Society for Laboratory Automation and Screening.
Biofocus DPI Ltd | Date: 2013-03-13
Novel imidazopyrazine compounds are disclosed that have a formula represented by the following: The compounds may be prepared as pharmaceutical compositions, and may be used for the prevention and treatment of a viral infection, in particular a HCV, HRV, Sb and/or CVB in a patient in need thereof.