Open AccessOptimization of Indazole-Based GSK-3 Inhibitors with Mitigated hERG Issue and In Vivo Activity in a Mood Disorder Model
Author(s) -
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 Ombrato
Publication year - 2020
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00633
Subject(s) - gsk 3 , herg , indazole , in vivo , pharmacology , mania , mood , mood disorders , adme , lipophilicity , chemistry , medicine , bipolar disorder , kinase , drug , biochemistry , biology , psychiatry , potassium channel , stereochemistry , anxiety , microbiology and biotechnology
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 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.