Optimization of Indazole-Based GSK-3 Inhibitors with Mitigated hERG Issue and In Vivo Activity in a Mood Disorder Model.

ABSTRACT: Bipolar disorders still represent a global unmet medical need and pose a requirement for novel effective treatments. In this respect, glycogen synthase kinase 3β (GSK-3β) aberrant activity has been linked to the pathophysiology of several disease conditions, including mood disorders. Therefore, the development of GSK-3β 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 li

SUBMITTER: Prati F 

PROVIDER: S-EPMC7236279 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature