- SMALL MOLECULE ACTIVATORS OF NICOTINAMIDE PHOSPHORIBOSYLTRANSFERASE (NAMPT) AND USES THEREOF
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Provided herein are small molecule activators of Nicotinamide Phosphoribosyltransferase (NAMPT), compositions comprising the compounds, and methods of using the compounds and compositions.
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- Selective targeting of dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (Dc-Sign) with mannose-based glycomimetics: Synthesis and interaction studies of bis(benzylamide) derivatives of a pseudomannobioside
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Dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) and Langerin are C-type lectins of dendritic cells (DCs) that share a specificity for mannose and are involved in pathogen recognition. HIV is known to use DC-SIGN on DCs to facilitate transinfection of T-cells. Langerin, on the contrary, contributes to virus elimination; therefore, the inhibition of this latter receptor is undesired. Glycomimetic molecules targeting DC-SIGN have been reported as promising agents for the inhibition of viral infections and for the modulation of immune responses mediated by DC-SIGN. We show here for the first time that glycomimetics based on a mannose anchor can be tuned to selectively inhibit DC-SIGN over Langerin. Based on structural and binding studies of a mannobioside mimic previously described by us (2), a focused library of derivatives was designed. The optimized synthesis gave fast and efficient access to a group of bis(amides), decorated with an azide-terminated tether allowing further conjugation. SPR inhibition tests showed improvements over the parent pseudomannobioside by a factor of 3-4. A dimeric, macrocyclic structure (11) was also serendipitously obtained, which afforded a 30-fold gain over the starting compound (2). The same ligands were tested against Langerin and found to exhibit high selectivity towards DC-SIGN. Structural studies using saturation transfer difference NMR spectroscopy (STD-NMR) were performed to analyze the binding mode of one representative library member with DC-SIGN. Despite the overlap of some signals, it was established that the new ligand interacts with the protein in the same fashion as the parent pseudodisaccharide. The two aromatic amide moieties showed relatively high saturation in the STD spectrum, which suggests that the improved potency of the bis(amides) over the parent dimethyl ester can be attributed to lipophilic interactions between the aromatic groups of the ligand and the binding site of DC-SIGN. Receptor targeting: For the first time glycomimetics based on a mannose anchor have been tuned to selectively inhibit DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin) over Langerin. Based on structural and binding studies of a mannobioside mimic previously described, a focused library of derivatives was designed (see figure). Copyright
- Varga, Norbert,Sutkeviciute, Ieva,Guzzi, Cinzia,McGeagh, John,Petit-Haertlein, Isabelle,Gugliotta, Serena,Weiser, J?rg,Angulo, Jesús,Fieschi, Franck,Bernardi, Anna
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supporting information
p. 4786 - 4797
(2013/05/21)
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- Synthesis and anticonvulsant activities of (R)-N-(4′-substituted) benzyl 2-acetamido-3-methoxypropionamides
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The structure-activity relationship (SAR) for the N-benzyl group in the clinical antiepileptic agent (R)-lacosamide [(R)-N-benzyl 2-acetamido-3- methoxypropionamide, (R)-3] has been explored. Forty-three compounds were prepared and then evaluated at the National Institute of Neurological Disorders and Stroke Anticonvulsant Screening Program for seizure protection in the maximal electroshock (MES) and subcutaneous Metrazol models. Comparing activities for two series of substituted aryl regioisomers (2′, 3′, 4′) showed that 4′-modified derivatives had the highest activity. Significantly, structural latitude existed at the 4′-site. The SAR indicated that nonbulky 4′-substituted (R)-3 derivatives exhibited superb activity, independent of their electronic properties. Activities in the MES test of several compounds were comparable with or exceeded that of (R)-3 and surpassed the activities observed for the traditional antiepileptic agents phenytoin, phenobarbital, and valproate. 2009 American Chemical Society.
- Salomé, Christophe,Salomé-Grosjean, Elise,Park, Ki Duk,Morieux, Pierre,Swendiman, Robert,DeMarco, Erica,Stables, James P.,Kohn, Harold
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supporting information; experimental part
p. 1288 - 1305
(2010/07/10)
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- NOVEL N-BENZYLAMIDE SUBSTITUTED DERIVATIVES OF 2-(ACYLAMIDO)ACETIC ACID AND 2-(ACYLAMIDO)PROPIONIC ACIDS: POTENT NEUROLOGICAL AGENTS
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A first aspect of the invention is a compound (sometimes also referred to herein as an "active agent" or "active compound") of Formula (I) or ( Ia): or a pharmaceutically acceptable salt or prodrug thereof. Compositions thereof and methods of using the same (e.g. for the treatment of a neurological disease) are also described.
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- N-ALKYL PYRROLES AS HMG-COA REDUCTASE INHIBITORS
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HMGCo-A reductase inhibitor compounds useful as hypocholesterolemic and hypolipidemic compounds are provided. Also provided are pharmaceutical compositions of the compounds. Methods of making and methods of using the compounds are also provided. Formula (I).
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Page/Page column 152
(2010/02/12)
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- Chemical Ionization Mass Spectrometry of Bifunctional Compounds. The Behaviour of Bifunctional Compounds on Protonation
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Positive-ion chemical ionization mass spectra were measured for simple bifunctional aromatic compounds of the type p-XCH2C6H4CH2Y, where X = NH2, NH(CH3) and N(CH3)2 and Y = OH and OCH3.For each compound, essentially only three peaks of ions, (1+), (1+) and (1+), appeared.The B/E constant linked-scan spectra showed that the stable non-decomposing (1+) had the proton only on the nitrogen-containing functional group.From these data, the relative amounts of total protonation, the ratio of N- and O-protonation and the fraction of fragmenting (1+) can be calculated.The ease of protonation (protonation sus ceptibility) and the reactivity (fragmentation capability) of the respective functional groups are discussed.
- Nakata, Hisao,Suzuki, Yumi,Shibata, Miyuki,Takahashi, Konomi,Konishi, Hideyuki,et al.
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p. 649 - 654
(2007/10/02)
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