Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 58, Issue 22, Pages 8920-8937Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b01208
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Novel treatments for bipolar disorder with improved efficacy and broader spectrum of activity are urgently needed. Glycogen synthase kinase 3 beta (GSK-3 beta) has been suggested to be a key player in the pathophysiology of bipolar disorder. A series of novel GSK-3 beta inhibitors having the common N-[(1-alkylpiperidin-4-yl)methyl]-1H-indazole-3-carboxamide scaffold were prepared taking advantage of an X-ray cocrystal structure of compound 5 with GSK-3 beta. We probed different substitutions at the indazole 5-position and at the piperidine-nitrogen to obtain potent ATP-competitive GSK-3 beta inhibitors with good cell activity. Among the compounds assessed in the in vivo PK experiments, 14i showed, after i.p. dosing, encouraging plasma PK profile and brain exposure, as well as efficacy in a mouse model of mania. Compound 14i was selected for further in vitro/in vivo pharmacological evaluation, in order to elucidate the use of ATP-competitive GSK-3 beta inhibitors as new tools in the development of new treatments for mood disorders
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