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Optimization of Indazole-Based GSK-3 Inhibitors with Mitigated hERG Issue and In Vivo Activity in a Mood Disorder Model.
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2020-03-24 , DOI: 10.1021/acsmedchemlett.9b00633 Federica Prati 1 , Rosa Buonfiglio 1 , Guido Furlotti 1 , Claudia Cavarischia 1 , Giorgina Mangano 1 , Rossella Picollo 1 , Laura Oggianu 1 , Anna di Matteo 1 , Silvana Olivieri 1 , Graziella Bovi 1 , Pier Francesca Porceddu 2 , Angelo Reggiani 2 , Beatrice Garrone 1 , Francesco Paolo Di Giorgio 1 , Rosella Ombrato 1
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2020-03-24 , DOI: 10.1021/acsmedchemlett.9b00633 Federica Prati 1 , Rosa Buonfiglio 1 , Guido Furlotti 1 , Claudia Cavarischia 1 , Giorgina Mangano 1 , Rossella Picollo 1 , Laura Oggianu 1 , Anna di Matteo 1 , Silvana Olivieri 1 , Graziella Bovi 1 , Pier Francesca Porceddu 2 , Angelo Reggiani 2 , Beatrice Garrone 1 , Francesco Paolo Di Giorgio 1 , Rosella Ombrato 1
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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.
中文翻译：
优化的基于吲唑的GSK-3抑制剂具有缓解的hERG问题和在情绪障碍模型中的体内活性。
躁郁症仍然代表着全球尚未满足的医疗需求，并提出了新颖有效治疗的要求。在这方面，糖原合酶激酶3β（GSK-3β）异常活性已与包括情绪障碍在内的几种疾病的病理生理联系在一起。因此，需要开发具有高体内功效和与高脑暴露有关的安全性的GSK-3β抑制剂。因此，我们先前已经报道了选择性的基于吲唑的GSK-3抑制剂1，在躁狂症的小鼠模型中显示出优异的功效。尽管临床前情况良好，类似物1在hERG离子通道上仍具有活性，阻止了其进一步发展。在此，我们描述了通过调节理化特性来改善脱靶效应的策略，例如亲脂性和碱性。这些努力导致了有效的抑制剂14，其具有降低的hERG亲和力，有希望的体外ADME特性，并且在体内情绪稳定剂模型中非常有效。
更新日期：2020-03-24
中文翻译：
优化的基于吲唑的GSK-3抑制剂具有缓解的hERG问题和在情绪障碍模型中的体内活性。
躁郁症仍然代表着全球尚未满足的医疗需求，并提出了新颖有效治疗的要求。在这方面，糖原合酶激酶3β（GSK-3β）异常活性已与包括情绪障碍在内的几种疾病的病理生理联系在一起。因此，需要开发具有高体内功效和与高脑暴露有关的安全性的GSK-3β抑制剂。因此，我们先前已经报道了选择性的基于吲唑的GSK-3抑制剂1，在躁狂症的小鼠模型中显示出优异的功效。尽管临床前情况良好，类似物1在hERG离子通道上仍具有活性，阻止了其进一步发展。在此，我们描述了通过调节理化特性来改善脱靶效应的策略，例如亲脂性和碱性。这些努力导致了有效的抑制剂14，其具有降低的hERG亲和力，有希望的体外ADME特性，并且在体内情绪稳定剂模型中非常有效。
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