Optimization of Indazole-Based GSK-3 Inhibitors with Mitigated hERG Issue and In Vivo Activity in a Mood Disorder Model

Abstract

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 offtarget 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.

Current progress, challenges and future prospects of indazoles as protein kinase inhibitors for the treatment of cancer

“…16). 93 Their studies suggested that the replacement of the (2-methoxyethyl)-4methylpiperidine group by oxanyl, oxolanyl, thiolanedionyl and thianedionyl groups reduced the lipophilicity of the resultant derivatives (33)(34)(35)(36)(37)(38)(39)(40)(41) and led to improved selectivity towards the human ether-à-go-go-related dene (hERG) by 41-500 fold compared to compound 40. Further, replacement of the diuorophenyl moiety with polar pyridinyl and alkoxysubstituted pyridinyl groups led to compounds (44a-f) with promising activities (hERG IC 50 > 40 mM), except for compounds 44b and 44c (hERG IC 50 ¼ 0.86 and 5.70 mM, respectively).…”

Discovery of Novel Imidazopyridine GSK-3β Inhibitors Supported by Computational Approaches

“…INDZ derivatives 1-6 were synthesized as previously described [17][18][19], whereas imidazo[1,5-a] pyridines 7-18 were prepared according to the linear synthetic routes depicted in Schemes 1 and 2. Specifically, IMID 1 derivatives 7-10 and 12 were obtained in a four-step synthesis starting from the commercially available 7-bromoimidazo[1,5-a]pyridine (Scheme 1).…”

“…Specifically, IMID 1 derivatives 7-10 and 12 were obtained in a four-step synthesis starting from the commercially available 7-bromoimidazo[1,5-a]pyridine (Scheme 1). 7-bromoimidazo[1,5-a]pyridine underwent Vilsmeier-Haack reaction in the presence of DMF and phosphorus oxychloride to provide the corresponding aldehyde (19). Subsequent silver nitrate-mediated oxidation led to the carboxylic acid 20, which was then coupled to 1-[1-(2-methoxyethyl)piperidin-4-yl]methanamine and 1-(oxan-4-yl)methanamine under standard carboxylic acid-amine coupling reaction to afford amides 21 and 22, respectively.…”

“…The INDZ core was previously identified as an attractive scaffold for the development of novel GSK-3β inhibitors [16][17][18][19]. Through in silico and crystallographic studies [16,17,19], it was found to bind in the ATP binding domain of GSK-3β enzyme between the N-and C-terminal lobes (Figure 2a).…”

“…On these premises, a discovery program started at Angelini Pharma with a computer-aided protocol based on structure-based virtual screening and similarity search, which led to the identification of the 1H-indazole-3-carboxamide moiety (INDZ) as a new scaffold for GSK-3β inhibition [16]. Subsequent optimization campaigns followed to optimize GSK-3β inhibition potency, as well as ADMET properties, and resulted in INDZ derivatives 1-6 [17][18][19] (Figure 1 and Table 1). Despite few derivatives showing promising in vitro profiles, enhanced blood brain barrier (BBB) penetration was still desirable to hinder CNS disorders.…”