- Indirubin core structure of glycogen synthase kinase-3 inhibitors as novel chemotype for intervention with 5-lipoxygenase
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The enzymes 5-lipoxygenase (5-LO) and glycogen synthase kinase (GSK)-3 represent promising drug targets in inflammation. We made use of the bisindole core of indirubin, present in GSK-3 inhibitors, to innovatively target 5-LO at the ATP-binding site for the design of dual 5-LO/GSK-3 inhibitors. Evaluation of substituted indirubin derivatives led to the identification of (3Z)-6-bromo-3-[(3E)-3-hydroxyiminoindolin-2-ylidene]indolin-2-one (15) as a potent, direct, and reversible 5-LO inhibitor (IC50 = 1.5 μM), with comparable cellular effectiveness on 5-LO and GSK-3. Together, we present indirubins as novel chemotypes for the development of 5-LO inhibitors, the interference with the ATP-binding site as a novel strategy for 5-LO targeting, and dual 5-LO/GSK-3 inhibition as an unconventional and promising concept for anti-inflammatory intervention.
- Pergola, Carlo,Gaboriaud-Kolar, Nicolas,Jest?dt, Nadine,K?nig, Stefanie,Kritsanida, Marina,Schaible, Anja M.,Li, Haokun,Garscha, Ulrike,Weinigel, Christina,Barz, Dagmar,Albring, Kai F.,Huber, Otmar,Skaltsounis, Alexios L.,Werz, Oliver
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p. 3715 - 3723
(2014/05/20)
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- Certain 1H-pyrrold[3,4-b]quinolin-1-one-9-amino-2,3-dihydro derivatives useful for treating anxiety
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The present invention comprises certain quinoline lactams of formula I; pharmaceutically acceptable salts of the compounds of formula I; pharmaceutical compositions containing a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of anxiety; and processes for the manufacture of the compounds of formula I, as well as intermediates for use in such manufacture.
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