345264-15-5Relevant academic research and scientific papers
Development of Bisindole-Substituted Aminopyrazoles as Novel GSK-3β Inhibitors with Suppressive Effects against Microglial Inflammation and Oxidative Neurotoxicity
Liu, Jian-Guo,Zhao, Danfeng,Gong, Qi,Bao, Fengxia,Chen, Wen-Wen,Zhang, Haiyan,Xu, Ming-Hua
, p. 3398 - 3408 (2020/11/26)
Development of glycogen synthase kinase-3β (GSK-3β) inactivation-centric agents with polypharmacological profiles is increasingly recognized as a promising therapeutic strategy against the multifactorial etiopathology of Alzheimer's disease (AD). In this respect, a series of disubstituted aminopyrazole derivatives were designed and synthesized as a new class of GSK-3β inhibitors. Most of these derivatives possess GSK-3β inhibitory activities with IC50 values in the micromolar ranges, among which bisindole-substituted aminopyrazole derivative 6h displayed moderate GSK-3β inhibition (IC50 = 1.76 ± 0.19 μM), and alleviative effects against lipopolysaccharide (LPS)-induced glial inflammation in BV-2 cells and glutamate-induced oxidative neurotoxicity in HT-22 cells. Further in vivo studies indicated that compound 6h had potent anti-inflammatory effect, by showing markedly reduced microglial activation and astrocyte proliferation in the brain of LPS-injected mice. Overall, the simultaneous modulation of 6h on multiple dysfunctions of disease network highlights this structural distinctively bisindole-substituted aminopyrazole could be a useful prototype for the discovery of novel therapeutic agents to tackle AD and other GSK-3β associated complex neurological syndromes.
Characterization of maleimide-based glycogen synthase kinase-3 (GSK-3) inhibitors as stimulators of steroidogenesis
Gunosewoyo, Hendra,Midzak, Andrew,Gaisina, Irina N.,Sabath, Emily V.,Fedolak, Allison,Hanania, Taleen,Brunner, Dani,Papadopoulos, Vassilios,Kozikowski, Alan P.
, p. 5115 - 5129 (2013/07/25)
Inhibition of GSK-3β has been well documented to account for the behavioral actions of the mood stabilizer lithium in various animal models of mood disorders. Recent studies have showed that genetic or pharmacological inhibition of GSK-3β resulted in anxiolytic-like and pro-social behavior. In our ongoing efforts to develop GSK-3β inhibitors for the treatment of mood disorders, SAR studies on maleimide-based compounds were undertaken. We present herein for the first time that some of these GSK-3β inhibitors, in particular analogues 1 and 9, were able to stimulate progesterone production in the MA-10 mouse tumor Leydig cell model of steroidogenesis without any significant toxicity. These two compounds were tested in the SmartCube behavioral assay and showed anxiolytic-like signatures following daily dose administration (50 mg/kg, ip) for 13 days. Taken together, these results support the hypothesis that GSK-3β inhibition could influence neuroactive steroid production thereby mediating the modulation of anxiety-like behavior in vivo.
HDAC INHIBITORS
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Page/Page column 57; 59-60, (2009/04/25)
The present invention provides hydroxamic acid compounds, and methods of preparation of these compounds. The present invention also relates to pharmaceutical compositions comprising the hydroxamic acid compounds. The present invention provides methods of treating a cell proliferative disorder, such as a cancer, by administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention.
Substituted 3-imidazo[1,2-a]pyridin-3-yl-4-(1,2,3,4-tetrahydro-[1,4] diazepino-[6,7,1-hi]indol-7-yl)pyrrole-2,5-diones as highly selective and potent inhibitors of glycogen synthase kinase-3
Engler, Thomas A.,Henry, James R.,Malhotra, Sushant,Cunningham, Brian,Furness, Kelly,Brozinick, Joseph,Burkholder, Timothy P.,Clay, Michael P.,Clayton, Joshua,Diefenbacher, Clive,Hawkins, Eric,Iversen, Philip W.,Li, Yihong,Lindstrom, Terry D.,Marquart, Angela L.,McLean, Johnathan,Mendel, David,Misener, Elizabeth,Briere, Daniel,O'Toole, John C.,Porter, Warren J.,Queener, Steven,Reel, Jon K.,Owens, Rebecca A.,Brier, Richard A.,Eessalu, Thomas E.,Wagner, Jill R.,Campbell, Robert M.,Vaughn, Renee
, p. 3934 - 3937 (2007/10/03)
Glycogen synthase kinase-3 (GSK3) is involved in signaling from the insulin receptor. Inhibitors of GSK3 are expected to effect lowering of plasma glucose similar to insulin, making GSK3 an attractive target for the treatment of type 2 diabetes. Herein we report the discovery of a series of potent and selective GSK3 inhibitors. Compounds 7-12 show oral activity in an in vivo model of type II diabetes, and 9 and 12 have desirable PK properties.
Preparation of novel aza-1,7-annulated indoles and their conversion to potent indolocarbazole kinase inhibitors
Al-awar, Rima S.,Ray, James E.,Hecker, Kyle A.,Joseph, Sajan,Huang, Jianping,Shih, Chuan,Brooks, Harold B.,Spencer, Charles D.,Watkins, Scott A.,Schultz, Richard M.,Considine, Eileen L.,Faul, Margaret M.,Sullivan, Kevin A.,Kolis, Stanley P.,Carr, Michael A.,Zhang, Faming
, p. 3925 - 3928 (2007/10/03)
The synthesis of novel aza-1,7-annulated indoles was achieved and these were converted to indolocarbazoles that proved to be potent kinase inhibitors. These compounds were also evaluated in a human colon carcinoma cell line and proved to be good antiproliferative agents.
PURINE DERIVATIVES AS KINASE INHIBITORS
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Page/Page column 28, (2008/06/13)
The present invention provides kinase inhibitors of Formula I.
