| Autor: |
Bernard-Gauthier, Vadim, Mossine, Andrew V., Knight, Ashley, Patnaik, Debasis, Zhao, Wen-Ning, Cheng, Chialin, Krishnan, Hema S., Xuan, Lucius L., Chindavong, Peter S., Reis, Surya A., Chen, Jinshan Michael, Shao, Xia, Stauff, Jenelle, Arteaga, Janna, Sherman, Phillip, Salem, Nicolas, Bonsall, David, Amaral, Brenda, Varlow, Cassis, Wells, Lisa, Martarello, Laurent, Patel, Shil, Liang, Steven H., Kurumbail, Ravi G., Haggarty, Stephen J., Scott, Peter J. H., Vasdev, Neil |
| Zdroj: |
Journal of Medicinal Chemistry; November 2019, Vol. 62 Issue: 21 p9600-9617, 18p |
| Abstrakt: |
Using structure-guided design, several cell based assays, and microdosed positron emission tomography (PET) imaging, we identified a series of highly potent, selective, and brain-penetrant oxazole-4-carboxamide-based inhibitors of glycogen synthase kinase-3 (GSK-3). An isotopologue of our first-generation lead, [3H]PF-367, demonstrates selective and specific target engagement in vitro, irrespective of the activation state. We discovered substantial ubiquitous GSK-3-specific radioligand binding in Tg2576 Alzheimer’s disease (AD), suggesting application for these compounds in AD diagnosis and identified [11C]OCM-44 as our lead GSK-3 radiotracer, with optimized brain uptake by PET imaging in nonhuman primates. GSK-3β-isozyme selectivity was assessed to reveal OCM-51, the most potent (IC50= 0.030 nM) and selective (>10-fold GSK-3β/GSK-3α) GSK-3β inhibitor known to date. Inhibition of CRMP2T514and tau phosphorylation, as well as favorable therapeutic window against WNT/β-catenin signaling activation, was observed in cells. |
| Databáze: |
Supplemental Index |
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