Substituted 3-Imidazo[1,2-<i>a</i>]pyridin-3-yl- 4-(1,2,3,4-tetrahydro-[1,4]diazepino- [6,7,1-<i>hi</i>]indol-7-yl)pyrrole-2,5-diones as Highly Selective and Potent Inhibitors of Glycogen Synthase Kinase-3

Ta, Engler; Henry,; Malhotra, Sushant; Cunningham, Brian; Furness, Kelly; Brozinick, Joseph T.; Tp, Burkholder; Mp, Clay; Clayton, Joshua R.; Diefenbacher, Clive; Hawkins, Eric D.; Pw, Iversen; Y, Li; Td, Lindstrom; Al, Marquart; McLean, Johnathan; Mendel, David; Misener, Elizabeth A.; Briere, Daniel A.; Jc, O'Toole; Wj, Porter; Queener, Stephen W.; Jk, Reel; Owens, Roland A.; Ra, Brier; Te, Eessalu; Wagner, Verena; Campbell, Rona; Vaughn, Renee

doi:10.1021/jm049768a

Cited by 95 publications

(50 citation statements)

References 29 publications

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“…Previous studies reported that the treatment of lithium, an inhibitor for both GSK3β enzymatic activity and inositol metabolism circuits, increased bone mass in animals with age-related osteoporosis and oophorectomy-induced osteoporosis394041. In this study, we found that wedelolactone directly inhibited the activity of GSK3β, suggesting that wedelolactone was an inhibitor of GSK3β (Fig.…”

Section: Discussionsupporting

confidence: 62%

Wedelolactone enhances osteoblastogenesis by regulating Wnt/β-catenin signaling pathway but suppresses osteoclastogenesis by NF-κB/c-fos/NFATc1 pathway

Zhang

Zhan

et al. 2016

Sci Rep

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Bone homeostasis is maintained by formation and destruction of bone, which are two processes tightly coupled and controlled. Targeting both stimulation on bone formation and suppression on bone resorption becomes a promising strategy for treating osteoporosis. In this study, we examined the effect of wedelolactone, a natural product from Ecliptae herba, on osteoblastogenesis as well as osteoclastogenesis. In mouse bone marrow mesenchymal stem cells (BMSC), wedelolactone stimulated osteoblast differentiation and bone mineralization. At the molecular level, wedelolactone directly inhibited GSK3β activity and enhanced the phosphorylation of GSK3β, thereafter stimulated the nuclear translocation of β-catenin and runx2. The expression of osteoblastogenesis-related marker gene including osteorix, osteocalcin and runx2 increased. At the same concentration range, wedelolactone inhibited RANKL-induced preosteoclastic RAW264.7 actin-ring formation and bone resorption pits. Further, wedelolactone blocked NF-kB/p65 phosphorylation and abrogated the NFATc1 nuclear translocation. As a result, osteoclastogenesis-related marker gene expression decreased, including c-src, c-fos, and cathepsin K. In ovariectomized mice, administration of wedelolactone prevented ovariectomy-induced bone loss by enhancing osteoblast activity and inhibiting osteoclast activity. Together, these data demonstrated that wedelolactone facilitated osteoblastogenesis through Wnt/GSK3β/β-catenin signaling pathway and suppressed RANKL-induced osteoclastogenesis through NF-κB/c-fos/NFATc1 pathway. These results suggested that wedelolacone could be a novel dual functional therapeutic agent for osteoporosis.

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Section: Discussionsupporting

confidence: 62%

Wedelolactone enhances osteoblastogenesis by regulating Wnt/β-catenin signaling pathway but suppresses osteoclastogenesis by NF-κB/c-fos/NFATc1 pathway

Zhang

Zhan

et al. 2016

Sci Rep

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“…To induce osteoblast differentiation, normal culture medium (NM, as described above) was supplemented with freshly added ascorbic acid (50 µg/ml; Merck Inc., Kenilworth, NJ), β‐glycerophosphate (5 mM; Sigma–Aldrich), and dexamethasone (0.1 µM; Sigma–Aldrich) with or without recombinant human BMP‐2, BMP‐ 6 (50 ng/ml; R&D Systems, Minneapolis, MN) or a specific GSK3β inhibitor (GIN; 10nM; kindly provided by Dr. Rawadi, Prostrakan, France; Engler et al25) Cell cultures were subjected randomly to either BMP‐2 or BMP‐6. The culture medium was replaced every 3 to 4 days.…”

Section: Methodsmentioning

confidence: 99%

Peri-prosthetic tissue cells show osteogenic capacity to differentiate into the osteoblastic lineage

et al. 2017

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During the process of aseptic loosening of prostheses, particulate wear debris induces a continuous inflammatory‐like response resulting in the formation of a layer of fibrous peri‐prosthetic tissue at the bone‐prosthesis interface. The current treatment for loosening is revision surgery which is associated with a high‐morbidity rate, especially in old patients. Therefore, less invasive alternatives are necessary. One approach could be to re‐establish osseointegration of the prosthesis by inducing osteoblast differentiation in the peri‐prosthetic tissue. Therefore, the aim of this study was to investigate the capacity of peri‐prosthetic tissue cells to differentiate into the osteoblast lineage. Cells isolated from peri‐prosthetic tissue samples (n = 22)−obtained during revision surgeries−were cultured under normal and several osteogenic culture conditions. Osteogenic differentiation was assessed by measurement of Alkaline Phosphatse (ALP), mineralization of the matrix and expression of several osteogenic genes. Cells cultured in osteogenic medium showed a significant increase in ALP staining (p = 0.024), mineralization of the matrix (p < 0.001) and ALP gene expression (p = 0.014) compared to normal culture medium. Addition of bone morphogenetic proteins (BMPs), a specific GSK3β inhibitor (GIN) or a combination of BMP and GIN to osteogenic medium could not increase ALP staining, mineralization, and ALP gene expression. In one donor, addition of GIN was required to induce mineralization of the matrix. Overall, we observed a high‐inter‐donor variability in response to osteogenic stimuli. In conclusion, peri‐prosthetic tissue cells, cultured under osteogenic conditions, can produce alkaline phosphatase and mineralized matrix, and therefore show characteristics of differentiation into the osteoblastic lineage. © 2016 The Authors. Journal of Orthopaedic Research published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 35:1732–1742, 2017.

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“…34 Sequential Boc protection of the secondary amine, tosylation of the hydroxyl group and sodium hydride-assisted cyclization 34 gave the intermediary 1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1- hi ]indoles 43a and 43b . Glyoxylation with ethyl chlorooxoacetate, condensation with benzofuran-3-yl-acetamide and subsequent Boc deprotection afforded the maleimides 24 and 25 .…”

Section: Chemistrymentioning

confidence: 99%

Characterization of Maleimide-Based Glycogen Synthase Kinase-3 (GSK-3) Inhibitors as Stimulators of Steroidogenesis

et al. 2013

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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 analogs 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, i.p.) 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.

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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

Cited by 95 publications

References 29 publications

Wedelolactone enhances osteoblastogenesis by regulating Wnt/β-catenin signaling pathway but suppresses osteoclastogenesis by NF-κB/c-fos/NFATc1 pathway

Wedelolactone enhances osteoblastogenesis by regulating Wnt/β-catenin signaling pathway but suppresses osteoclastogenesis by NF-κB/c-fos/NFATc1 pathway

Peri-prosthetic tissue cells show osteogenic capacity to differentiate into the osteoblastic lineage

Characterization of Maleimide-Based Glycogen Synthase Kinase-3 (GSK-3) Inhibitors as Stimulators of Steroidogenesis

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