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Optimization of Indazole-Based GSK‑3 Inhibitors with Mitigated hERG Issue and In Vivo Activity in a Mood Disorder Model
journal contribution
posted on 2020-03-27, 19:37 authored by Federica Prati, Rosa Buonfiglio, Guido Furlotti, Claudia Cavarischia, Giorgina Mangano, Rossella Picollo, Laura Oggianu, Anna di Matteo, Silvana Olivieri, Graziella Bovi, Pier Francesca Porceddu, Angelo Reggiani, Beatrice Garrone, Francesco Paolo Di Giorgio, Rosella OmbratoBipolar 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
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.
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glycogen synthase kinase 3βVivo Activityvivo modelMood Disorder Model Bipolar disordershERG affinityGSK -3β inhibitorsADME propertiesindazole-based GSK -3 inhibitor 1Mitigated hERG Issuevivo efficacymood stabilizerhERG ion channelinhibitor 14off-target liabilitybrain exposuremood disordersmouse modelanalog 1physicochemical propertiesdisease conditionssafety profile
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