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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
Journal of medicinal chemistry, 11/2019, Letnik: 62, Številka: 21Journal Article
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, 3HPF-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 11COCM-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 CRMP2T514 and tau phosphorylation, as well as favorable therapeutic window against WNT/β-catenin signaling activation, was observed in cells.
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Dostop do baze podatkov JCR je dovoljen samo uporabnikom iz Slovenije. Vaš trenutni IP-naslov ni na seznamu dovoljenih za dostop, zato je potrebna avtentikacija z ustreznim računom AAI.
Leto | Faktor vpliva | Izdaja | Kategorija | Razvrstitev | ||||
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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Povezave do osebnih bibliografij avtorjev | Povezave do podatkov o raziskovalcih v sistemu SICRIS |
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Vir: Osebne bibliografije
in: SICRIS
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