6tcu

Glycogen synthase kinase-3 beta (GSK3b) in complex with ligand 1

spinqualitylabelsall models 6tcu, resolution 2.14Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.14Å Ligands: ACT, N1Q, PTR Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Bipolar disorders still represent a global unmet medical need and pose a requirement for novel effective treatments. In this respect, glycogen synthase kinase 3beta (GSK-3beta) aberrant activity has been linked to the pathophysiology of several disease conditions, including mood disorders. Therefore, the development of GSK-3beta inhibitors with good in vivo efficacy and safety profile associated with high brain exposure is required. Accordingly, we have previously reported the selective indazole-based GSK-3 inhibitor 1, which showed excellent efficacy in a mouse model of mania. Despite the favorable preclinical profile, analog 1 suffered from activity at the hERG ion channel, which prevented its further progression. Herein, we describe our strategy to improve this off-target liability through modulation of physicochemical properties, such as lipophilicity and basicity. These efforts led to the potent inhibitor 14, which possessed reduced hERG affinity, promising in vitro ADME properties, and was very effective in a mood stabilizer in vivo model. Optimization of Indazole-Based GSK-3 Inhibitors with Mitigated hERG Issue and In Vivo Activity in a Mood Disorder Model.,Prati F, Buonfiglio R, Furlotti G, Cavarischia C, Mangano G, Picollo R, Oggianu L, di Matteo A, Olivieri S, Bovi G, Porceddu PF, Reggiani A, Garrone B, Di Giorgio FP, Ombrato R ACS Med Chem Lett. 2020 Mar 24;11(5):825-831. doi:, 10.1021/acsmedchemlett.9b00633. eCollection 2020 May 14. PMID:32435391 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Glycogen synthase kinase 3 3D structures

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