Hit Optimization of 5-Substituted-N-(piperidin-4-ylmethyl)-1H-indazole-3-carboxamides: Potent Glycogen Synthase Kinase-3 (GSK-3) Inhibitors with in Vivo Activity in Model of Mood Disorders

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• 作者：Guido Furlotti ; Maria Alessandra Alisi ; Nicola Cazzolla ; Patrizia Dragone ; Lucia Durando ; Gabriele Magar貌 ; Francesca Mancini ; Giorgina Mangano ; Rosella Ombrato ; Marco Vitiello ; Andrea Armirotti ; Valeria Capurro ; Massimiliano Lanfranco ; Giuliana Ottonello ; Maria Summa ; Angelo Reggiani
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：November 25, 2015
• 年：2015
• 卷：58
• 期：22
• 页码：8920-8937
• 全文大小：767K
• ISSN：1520-4804

文摘

Novel treatments for bipolar disorder with improved efficacy and broader spectrum of activity are urgently needed. Glycogen synthase kinase 3尾 (GSK-3尾) has been suggested to be a key player in the pathophysiology of bipolar disorder. A series of novel GSK-3尾 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尾. We probed different substitutions at the indazole 5-position and at the piperidine-nitrogen to obtain potent ATP-competitive GSK-3尾 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尾 inhibitors as new tools in the development of new treatments for mood disorders.