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. 2020 Mar 24;11(5):825–831. doi: 10.1021/acsmedchemlett.9b00633

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

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 †,*
PMCID: PMC7236279  PMID: 32435391

Abstract

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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.

Keywords: GSK-3β, kinase inhibitor, hERG, mood disorders, indazoles

Discovered in the late 1970s, glycogen synthase kinase 3 (GSK-3) is a ubiquitous, multifunctional, and constitutively active serine/threonine kinase.1 Initially identified as a key regulator of insulin-dependent glycogen synthesis, it became an attractive drug target when its role in insulin signal transduction and regulation of tau protein phosphorylation was discovered.2 Similarly to other kinases, GSK-3 transfers phosphate groups from ATP to Ser/Thr of specific substrates, thus regulating a plethora of physiological functions and cellular events, such as insulin pathway, Wnt signaling pathway, cell division, survival and death, neuronal development, and transcription.3−5 In mammalian tissues, GSK-3 is expressed as the two isoforms GSK-3α and GSK-3β with molecular weights of about 51 and 47 kDa, respectively. These paralogs share nearly 98% homology in their kinase domain and show sequence differences elsewhere in the protein.6 The catalytic activity of GSK-3β/α is regulated by post-translational phosphorylation at two possible sites: Ser9/21 and Tyr216/279 for inactivation and activation processes, respectively.7

GSK-3β is widespread in many tissues with maximum levels found in the central nervous system (CNS), suggesting a fundamental role in neuronal signaling pathways. It modulates neuronal function in terms of neurogenesis, synaptic plasticity, neuronal structure, and neuronal survival and death.8

In resting conditions GSK-3β is functionally inhibited by upstream mechanisms while an aberrant activity has been reported in neurological or neurodevelopmental diseases such as neurodegenerative disorders (Alzheimer’s and Parkinson’s diseases), bipolar disorder, depression, and Fragile X syndrome.9−12 Moreover, clinical, genetic, and pharmacological studies suggest that GSK-3β inhibition may attenuate signaling dysfunction in psychiatric disorders. Also, it has been proved that lithium, the first-line treatment for bipolar disorder, inhibits GSK-3β kinase activity through two mechanisms: directly by competition with magnesium and indirectly by increasing inhibitory phosphorylation of GSK-3β at the Ser9 site.13

Boosted by such strong evidence, the interest of research groups and pharmaceutical companies to discover novel GSK-3β inhibitors has considerably increased over the years. Indeed, several publications have detailed the identification of GSK-3β inhibitors, with ATP competitive or uncompetitive mechanism of action.14−16 Despite the long-standing effort in developing novel therapeutics, no GSK-3β inhibitor is available on the market yet, and tideglusib remains one of the most advanced GSK-3β inhibitors under clinical investigation.17

In this scenario, the Angelini research group has previously reported on a virtual screening campaign that led to the discovery of the 1H-indazole-3-carboxamide scaffold as a novel structural class of ATP-competitive GSK-3β inhibitors.18 Subsequent optimization efforts provided analog 1 (Figure 1), which showed potent enzymatic and cellular GSK-3β inhibitory activity, a favorable kinase selectivity profile, and encouraging pharmacokinetic parameters to be progressed to preclinical behavioral studies.19 Importantly, compound 1 also exhibited excellent efficacy as mood-stabilizer in a mouse model of mania.19

Figure 1.

Figure 1

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Exploration of R1 and R2 groups around the 1H-indazole-3-carboxamide core of compound 1 to enhance hERG selectivity.

Unfortunately, compound 1 showed human ether-a-go-go related gene (hERG) liability. In fact, it turned out to be a potent GSK-3β and hERG inhibitor to the same extent (Figure 1 and Table 1). The blockade of this ion channel can be the concurrent cause of a severe tachyarrhythmia (torsades de points), which is recognized as a very dangerous side effect of drugs referred to as drug-induced long-QT syndrome, eventually leading to sudden cardiac death.20 Therein laid the need to identify novel GSK-3β inhibitors which retained the overall favorable in vitro/in vivo profile of 1 while mitigating the hERG blockade risk.

Table 1. SAR Exploration at R1 and R2 Positions of the 1H-Indazole-3-carboxamide Core.

graphic file with name ml9b00633_0006.jpg

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a

IC50 values were calculated from data points obtained as average of duplicate wells. Tables with a complete list of IC50 values and 95% confidence intervals are available in the Supporting Information (Tables S2 and S3).

b

cLogP and pKa values were calculated using ACD/Percepta 2017.2.

c

Reference compound.

In the present article, we describe the structure–activity relationships (SAR) of novel derivatives 2–16 starting from 1, where functional groups were introduced around the 1H-indazole-3-carboxamide scaffold to enhance GSK selectivity versus hERG. These efforts led to compound 14, which exhibited good GSK-3β inhibitory potency combined with a promising ADMET profile to be assessed in a preclinical model of mood disorders.

Compounds 2–16 were prepared according to the synthetic routes depicted in Scheme 1. Derivatives 2–12 were obtained in a two-step synthesis involving standard carboxylic acid-amine coupling reaction between 5-Br-indazole-3-carboxylic acid and the selected primary amines to afford the corresponding 5-Br-indazole-3-carboxamide intermediates 17–25, which were then coupled with the desired boronic acids to provide the target compounds. Conversely, the alkoxy-substituted pyridinyl derivatives 13–16 were synthesized by the additional conversion of the 5-bromo-N-[(oxan-4-yl)methyl]-indazole-3-carboxamide 17 to the corresponding boronic ester 26 and subsequent Suzuki coupling with the proper aryl bromides.

Scheme 1. Synthesis of Compounds 2–16.

Scheme 1

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Reagents and conditions: (a) NH2R1, HOBt, DCC, DMF, rt for 17 and 21. (b) NH2R1, HOBt, EDC.HCl, DMF, rt for 18–20 and 22–25. (c) R2B(OH)2, Pd(dppf)Cl2, Cs2CO3, dioxane/water, MW 130 °C for 2–10. (d) R2B(OH)2 or R2Br, Pd(dppf)Cl2, CsF, dioxane/water 100 °C for 11–15. (e) bis(pinacolato)diboron, Pd(dppf)Cl2, KOAc, dioxane, 100 °C. (f) R2Br, Pd(PPh3)4, Na2CO3, DMF/water, 100 °C for 16.

The drug design strategy toward analogs 2–16 was supported by the high-resolution (2.14 Å) X-ray crystal structure of 1 bound within the ATP binding pocket of GSK-3β kinase (PDB ID: 6TCU). Structural data revealed that the hydrogen-bond donor–acceptor–donor motif embedded within the indazole carboxamide core is anchored to the hinge domain via a tridentate hydrogen-bond interaction (dashed lines in Figure 2). In detail, the indazole NH-1 and N-2 form two hydrogen bonds with the backbone carbonyl group of Asp133 and the backbone NH of Val135 of the hinge region, respectively. The third hydrogen bond interaction, through the NH of the carboxamide group, engages the carbonyl of Val135. The piperidine moiety is oriented toward the guanidine group of Arg141 wholly exposed to the solvent-accessible part of the binding pocket. Finally, the di-F-phenyl ring seats with the two fluorine atoms pointing toward the catalytic Lys85.

Figure 2.

Figure 2

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X-ray cocrystal structure of GSK-3β kinase inhibitor 1 (PDB ID: 6TCU). Compound and protein are shown in green and gray, respectively. Hydrogen bonds are represented as yellow dashed lines. For the sake of clarity, some portions of the protein and water molecules have been omitted.

These data suggested that the 1H-indazole-3-carboxamide core of 1 was strongly implicated in crucial interactions for the inhibitor binding affinity and potency, whereas the (2-methoxyethyl)-4-methylpiperidine chain and di-F-phenyl ring were possibly involved in less tight binding patterns and could have been potentially replaced without affecting GSK-3β activity. Additionally, it was rationalized that the basicity of the piperidine nitrogen (pKa = 8.40) in combination with the lipophilic nature of the di-F-phenyl moiety of 1 was likely responsible for its interaction with the hERG channel. Indeed, the unfavorable effects of both positive ionizable groups and high lipophilicity on hERG blocking activity have been extensively studied.21 In light of that, we readily depicted the critical parts of 1 to be modified in this optimization campaign, being the positively charged piperidine group (R1) and di-F-phenyl ring (R2), while keeping the central 1H-indazole-3-carboxamide (Figure 1).

On these premises, exploration of different R1 and R2 groups and fine-tuning of physicochemical properties to mitigate the hERG related QT prolongation risk, as well as allow for suitable CNS permeation, were investigated. Particularly, the prospective design of novel compounds that could exhibit favorable alignment of ADMET attributes and cross the blood-brain barrier was supported by the CNS multiparameter optimization (CNS-MPO) desirability tool22 (Table S1).

SAR studies toward the replacement of the solvent-exposed (2-methoxyethyl)-4-methylpiperidine to modulate the compound basicity (pKa) by concomitantly lowering the lipophilicity (cLogP) revealed that the oxanyl, oxolanyl, thianedionyl, and thiolanedionyl moieties (compounds 2–10 in Table 1) were well tolerated. Indeed, for compounds 2–10, with pKa values around 2 and cLogP between 1.45 and 3.11, enzymatic activity against GSK-3β was retained in the nanomolar range, whereas hERG liability was significantly reduced (1.8 μM ≤ hERG IC50 ≤ 22.3 μM), resulting in an approximate 41–500-fold enhancement in hERG selectivity with respect to 1.

Based on these encouraging data, evaluation of different R2 groups was also performed. In particular, compound 2 (hERG IC50/GSK-3β IC50 = 286 and cLogP = 3.10) was considered a suitable starting point for the exploration strategy. Indeed, despite not being the most hERG selective derivative of the series, it showed: (i) no chiral centers, thus avoiding stereochemistry issues to be addressed early in the drug discovery process,23 and (ii) cLogP value suitable for further fine-tuning, while maintaining appropriate physicochemical requirements for CNS penetration. Accordingly, the di-F-phenyl moiety of 2 was replaced with more polar pyridinyl and alkoxy-substituted pyridinyl groups, resulting in derivatives 11–16. Compounds 11–16 showed lower cLogP values (1.06–2.56) than 2, associated with promising profiles in terms of both primary and off-target activities (Table 1). Specifically, all pyridinyl derivatives showed hERG IC50 > 40 μM, except for analogs 12 and 13. Compounds 12 and 13, in spite of the low pKa and cLogP values, displayed hERG IC50 = 0.86 and 5.7 μM, respectively, suggesting that discrete structural modifications also played an important role in modulating hERG binding.21 Notably, the (pyridin-3-yl)methanol derivative 14 with a cLogP of 1.06 resulted in the most interesting compound of the series and exhibited excellent GSK-3β inhibitory potency (IC50 = 0.004 μM), hERG IC50 > 100 μM, and a selectivity index hERG IC50/GSK-3β IC50 > 25000. Importantly, compound 14 turned out to be even more potent than reference ATP-competitive GSK-3β inhibitors AR-A014418 (IC50 = 0.104 μM)24 and AZD1080 (Ki = 0.031 μM).25

Taking advantage of the solved X-ray structure described above (PDB ID: 6TCU), a ligand docking study and a subsequent 500 ns molecular dynamics (MD) simulation were applied to investigate the binding mode and the stability of 14 in complex with GSK-3β kinase (Figure S1). As shown from an MD snapshot (Figure 3), the small molecule retained the same key interaction pattern of the parent compound 1. Specifically, the 1H-indazole-3-carboxamide core established persistent H-bond interactions with the Asp133 and Val135 backbone along the entire simulation, and the R2 pyridine nitrogen formed a H-bond with the catalytic Lys85. Direct or water-mediated H-bond interactions between the 14 hydroxyl group and Asp200 or Gln185 were also found. Furthermore, the R1 oxanyl group was oriented toward the solvent-exposed region without tight bonds with GSK-3β residues (see the Supporting Information for more details).

Figure 3.

Figure 3

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Representative MD snapshot of 14 in complex with GSK-3β kinase (PDB ID: 6TCU). Compound and protein are shown in yellow and gray, respectively. Hydrogen bonds are represented as orange dashed lines. For the sake of clarity, some portions of the protein have been omitted.

Compound 14 was further evaluated for activity in a whole cell tau phosphorylation assay, using recombinant human embryonic kidney (HEK) phospho-tau (p-tau) expressing cells. It showed cellular inhibitory effect in the single-digit micromolar range (IC50 = 3.4 μM) and no sign of toxicity up to 30 μM (Table 2). A large drop-off in enzyme versus cell activity was observed, but whole cell potency was still comparable with reference GSK-3β inhibitors.24

Table 2. Cellular Tau Phosphorylation Inhibition Result and In Vitro ADME Parameters for Compound 14.

    PPB @10 μM
 Microsomal stability @10 μM
 Human CYP450 inhibition (%) @10 μM
HEK p-tau IC50 (μM)a Acq. sol. PBS, pH = 7.4 (μM) Human bound (%) Mouse bound (%) Human t1/2 (min) Mouse t1/2 (min) 3A4 2D6 2C9 2C8 2C19 2B6
3.4b 200 82 56 >60 >60 4 5 31 16 30 –20
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a

IC50 values were calculated from data points obtained as average of quadruplicate wells.

b

95% confidence interval is 2.3–5.1 μM.

Compound 14 was also tested in a panel of in vitro ADME assays, where it displayed excellent properties (Table 2). Notably, analog 14 had high aqueous solubility in PBS buffer at pH = 7.4 and moderate protein plasma binding (PPB) in both analyzed species (human and mouse). The compound also demonstrated elevated stability in human and mouse microsomes and low inhibition of selected CYP450 human enzymes.

Based on the favorable in vitro profile, compound 14 was progressed to in vivo pharmacokinetic (PK) studies, with sampling collection performed at 0.5, 1, 2, 4, and 7 h postdose. The PK parameters of 14, evaluated after intraperitoneal administration (ip) at 10 mg/kg in mice, are summarized in Table 3.

Table 3. In Vivo PK Parameters for Compound 14 in Mice (10 mg/kg, ip).

Plasma
 Brain
tmax (h) Cmax (ng/mL) AUC0–t (h·ng/mL) AUC0–∞ (h·ng/mL) t1/2 (h) Cmax (ng/g)
0.5 949.4 781.29 791.35 2.0 21.1
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Despite suboptimal exposure levels, compound 14 was advanced for evaluation in a mice amphetamine study. This in vivo efficacy model is supposed to mimic the hyperactivity component of bipolar disorder. The test consists of two main steps: (i) after an initial habituation phase, mice are treated with the compound under investigation and then placed in the empty open field and recorded for motility for 15 min to assess the compound effect of spontaneous motility (drug treatment, Figure 4a), (ii) mice are injected with amphetamine, placed back in the box and recorded for motility for additional 90 min to evaluate the reversal of the amphetamine effect (amphetamine treatment, Figure 4b).19 Previously tested reference GSK-3β inhibitors LiCl, TDZD-8, and parent compound 1 were very effective in blocking amphetamine hyperactivity when given ip.19 Nevertheless, at the highest doses administered, the three compounds also inhibited spontaneous locomotor activity, possibly due to sedative effects.19 Compound 14 was tested in the range of doses between 3 and 30 mg/kg, and dose-dependent inhibition of amphetamine induced hypermotility was observed (Figure 4b). The first effective dose was 10 mg/kg, while the response was maximal at 30 mg/kg and similar to that reported for LiCl (50 mg/kg), TDZD-8 (30 mg/kg), and compound 1 (3 mg/kg).19 Importantly, contrary to the three tested reference inhibitors, derivative 14 showed no inhibition of spontaneous motility at any of the doses tested.

Figure 4.

Figure 4

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Effect of compound 14 on (a) spontaneous motility (drug treatment) and (b) amphetamine hyperactivity (amphetamine treatment). Each bar is the average ± SEM (n = 8 each group). *p < 0.05 versus amphetamine. One way analysis of variance (ANOVA) followed by Bonferroni post hoc test was used as statistical test.

The kinome selectivity of 14 was also assessed in an assay panel of 42 representative kinases at 10 μM (Table S4). For 19 kinases, showing more than 50% inhibition at this concentration, the IC50 determination was performed (Table S5). In this further characterization, compound 14 exhibited higher than 60-fold selectivity for GSK-3β over the other kinases, with the only exception of CDK2, CLK1, DYRK1a, GRK2 (ADRBK1), GSK-3α, and LynB (Table 4). Despite the overall promising selectivity profile, compound 14 displayed IC50 values < 0.010 μM against GSK-3α, DYRK1a, and LynB, possibly suggesting a nonselective binding toward these enzymes. However, based on available literature, none of the kinases listed in Table 4 have been specifically related to mood disorders, and they are not foreseen to affect 14’s efficacy in in vivo pharmacological models.26−34

Table 4. GSK-3β Kinase Selectivity of Compound 14 over Other Kinases.

Kinase IC50 (μM) Selectivity ratio (vs GSK-3β)
h-GSK-3β 0.004 1
h-GSK-3α <0.010 <2.5
h-DYRK1a <0.010 <2.5
h-LynB <0.010 <2.5
h-GRK2 (ADRBK1) 0.011 2.8
h-CLK1 0.013 3.3
h-CDK2 0.027 6.8
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In conclusion, we reported herein efforts to mitigate the hERG ion channel binding activity of lead compound 1, while retaining the favorable in vitro and in vivo profile. The cornerstone of the strategy to identify more promising GSK-3β inhibitors for advancement was to reduce the overall lipophilicity and basicity, which were identified as key contributors to the lack of selectivity versus the hERG channel for compound 1. Toward this end, structure-enabled design suggested the exploration of polar substituents with reduced pKa values at the R1 and R2 positions of the 1H-indazole-3-carboxamide core. This approach, which progressively improved the hERG safety margins of obtained compounds, resulted in compound 14 with good enzymatic and cellular GSK-3β inhibitory potency, reduced hERG activity, promising in vitro ADME properties, and a favorable kinase selectivity profile. Despite the poor exposure levels, compound 14 also showed efficacy and complete reversal of amphetamine hypermotility with no sedative effects in an in vivo efficacy model of mania.

These encouraging results suggest that the current class of 1H-indazole-3-carboxamide GSK-3β inhibitors may serve as the basis for further optimization toward compounds with improved pharmacokinetics to be advanced into the drug development pipeline and provide new effective treatments for mood disorder therapy.

Acknowledgments

We acknowledge Lucia Durando for fruitful discussion, Francesca Mancini for her support in biological data generation, and Daniele Frollano and Martina Bischetti for providing analytical data.

Glossary

Abbreviations

CNS

central nervous system

CNS-MPO

CNS multiparameter optimization

GSK-3

glycogen synthase kinase 3

HEK

human embryonic kidney

hERG

ether-a-go-go related gene

MD

molecular dynamics

PK

pharmacokinetic

PPB

protein plasma binding

p-tau

phospho-tau

SAR

structure–activity relationships

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.9b00633.

  • Supplementary Figure S1 and Tables S1–S5; synthesis of intermediates 17–26 and final compounds 2–16; X-ray crystal structure of GSK-3β kinase in complex with compound 1; docking and MD protocols; GSK-3β, hERG, cell tau phosphorylation, and in vitro ADME assay details; PK and PD study protocols; kinome selectivity details; 1H NMR and 13C NMR spectra and HPLC analysis data of final compounds (PDF)

Accession Codes

The PDB code is as follows: 6TCU.

Author Contributions

All authors have given approval to the final version of the manuscript.

The authors declare no competing financial interest.

Supplementary Material

ml9b00633_si_001.pdf (2.5MB, pdf)

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