A model method: A strategy that combines a knowledge-based insilico design approach and the development of novel activity-based probes (ABPs) for the detection of endogenous diacylglycerol lipase-α ...(DAGL-α) is presented. This approach resulted in the rapid identification of new DAGL-α inhibitors with high selectivity in the brain proteome. ABPP=activity-based protein profiling.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Inhibitors of diacylglycerol lipases and α,β-hydrolase domain containing protein 6 (ABHD6) are potential leads for the development of therapeutic agents for metabolic and neurodegenerative disorders. ...Here, we report the enantioselective synthesis and structure activity relationships of triazole ureas featuring chiral, hydroxylated 2-benzylpiperidines as dual inhibitors of DAGLα and ABHD6. The chirality of the carbon bearing the C2 substituent, as well as the position of the hydroxyl (tolerated at C5, but not at C3) has profound influence on the inhibitory activity of both DAGLα and ABHD6, as established using biochemical assays and competitive activity-based protein profiling on mouse brain extracts.
The enantioselective synthesis and structure-activity relationships of deoxy-iminosugar-based triazole ureas as dual inhibitors of DAGLα and ABHD6 were reported.
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IJS, KILJ, NUK, UL, UM, UPUK
The enantioselective synthesis and structure–activity relationships of deoxy-iminosugar-based triazole ureas as dual inhibitors of DAGLα and ABHD6 were reported.
Inhibitors of diacylglycerol lipases ...and α,β-hydrolase domain containing protein 6 (ABHD6) are potential leads for the development of therapeutic agents for metabolic and neurodegenerative disorders. Here, we report the enantioselective synthesis and structure activity relationships of triazole ureas featuring chiral, hydroxylated 2-benzylpiperidines as dual inhibitors of DAGLα and ABHD6. The chirality of the carbon bearing the C2 substituent, as well as the position of the hydroxyl (tolerated at C5, but not at C3) has profound influence on the inhibitory activity of both DAGLα and ABHD6, as established using biochemical assays and competitive activity-based protein profiling on mouse brain extracts.
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IJS, KILJ, NUK, UL, UM, UPUK
Komplex: In einer hochkonvergenten Synthese, die eine Sonogashira‐Kupplung zur Verbindung eines phenolischen Trisaccharids mit dem Phthiocerol enthält, wurde das Glykolipid PGL‐tb1 aus der äußeren ...Membran von hypervirulenten Mycobacterium‐tuberculosis‐Stämmen zum ersten Mal hergestellt. Mit asymmetrischen kupferkatalysierten 1,4‐Additionen an ungesättigte Thioester und cyclische Enone wurden die Methylgruppen eingeführt.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
A model method: A strategy that combines a knowledge-based insilico design approach and the development of novel activity-based probes (ABPs) for the detection of endogenous diacylglycerol ...lipase-alpha (DAGL-alpha) is presented. This approach resulted in the rapid identification of new DAGL-alpha inhibitors with high selectivity in the brain proteome. ABPP=activity-based protein profiling.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The cannabinoid CB
receptor (CB
R) represents a promising therapeutic target for various forms of tissue injury and inflammatory diseases. Although numerous compounds have been developed and widely ...used to target CB
R, their selectivity, molecular mode of action and pharmacokinetic properties have been poorly characterized. Here we report the most extensive characterization of the molecular pharmacology of the most widely used CB
R ligands to date. In a collaborative effort between multiple academic and industry laboratories, we identify marked differences in the ability of certain agonists to activate distinct signalling pathways and to cause off-target effects. We reach a consensus that HU910, HU308 and JWH133 are the recommended selective CB
R agonists to study the role of CB
R in biological and disease processes. We believe that our unique approach would be highly suitable for the characterization of other therapeutic targets in drug discovery research.
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