- Design, synthesis and biological evaluation of 7-chloro-9h-pyrimido[4,5-b]indole-based glycogen synthase kinase-3β inhibitors
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Glycogen synthase kinase-3β (GSK-3β) represents a relevant drug target for the treatment of neurodegenerative pathologies including Alzheimer’s disease. We herein report on the optimization of a novel class of GSK-3β inhibitors based on the tofacitinib-derived screen hit 3-((3R,4R)-3-((7-chloro-9H-pyrimido[4,5-b]indol-4-yl)(methyl)amino)-4-methylpiperidin-1-yl)-3-oxopropanenitrile (1). We synthesized a series of 19 novel 7-chloro-9H-pyrimido[4,5-b]indole-based derivatives and studied their structure–activity relationships with focus on the cyanoacetyl piperidine moiety. We unveiled the crucial role of the nitrile group and its importance for the activity of this compound series. A successful rigidization approach afforded 3-(3aRS,7aSR)-(1-(7-chloro-9H-pyrimido[4,5-b]indol-4-yl)octahydro-6H-pyrrolo[2,3-c]pyridin-6-yl)-propanenitrile (24), which displayed an IC50 value of 130 nM on GSK-3β and was further characterized by its metabolic stability. Finally, we disclosed the putative binding modes of the most potent inhibitors within the ATP binding site of GSK-3β by 1 μs molecular dynamics simulations.
- Andreev, Stanislav,Pantsar, Tatu,Ansideri, Francesco,Kudolo, Mark,Forster, Michael,Schollmeyer, Dieter,Laufer, Stefan A.,Koch, Pierre
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- AMIDE DERIVATIVES HAVING MULTIMODAL ACTIVITY AGAINST PAIN
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The present invention relates to amide derivatives having dual pharmacological activity towards both the sigma (σ) receptor, and the μ-opioid receptor, to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to t
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- Discovery of a series of aminopiperidines as novel iNOS inhibitors
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Nitric oxide (NO), a mediator of various physiological and pathophysiological processes, is synthesized by three isozymes of nitric oxide synthase (NOS). Potential candidate clinical drugs should be devoid of inhibitory activity against endothelial NOS (eNOS), since eNOS plays an important role in maintaining normal blood pressure and flow. A new series of aminopiperidines as potent inhibitors of iNOS were identified from a HTS lead. From this study, we identified compound 33 as a potent iNOS inhibitor, with >25-fold selectivity over eNOS and 16-fold selectivity over nNOS.
- Bourdonnec, Bertrand Le,Leister, Lara K.,Ajello, Christopher A.,Cassel, Joel A.,Seida, Pamela R.,O'Hare, Heather,Gu, Minghua,Chu, Guo-Hua,Tuthill, Paul A.,DeHaven, Robert N.,Dolle, Roland E.
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p. 336 - 343
(2008/09/18)
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- SUBSTITUTED 4,5,6,7-TETRAHYDRO-BENZOTHIAZOL-2-YLAMINE COMPOUNDS
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The invention relates to substituted 4,5,6,7-tetrahydro-benzothiazol-2-ylamine compounds, to methods for their production, to medicaments containing said compounds and to the use of said compounds for producing medicaments.
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Page/Page column 72
(2010/02/13)
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