Small-Molecule Inhibitors of GSK-3: Structural Insights and Their Application to Alzheimer's Disease Models

Kramer, Thomas; Schmidt, Boris; Lo Monte, Fabio

doi:https://doi.org/10.1155/2012/381029

International Journal of Alzheimer’s Disease

On this page

Abstract Introduction Abbreviations References Copyright Related Articles

Review Article | Open Access

Volume 2012 | Article ID 381029 | https://doi.org/10.1155/2012/381029

Small-Molecule Inhibitors of GSK-3: Structural Insights and Their Application to Alzheimer's Disease Models

Thomas Kramer,¹Boris Schmidt,¹and Fabio Lo Monte¹

Academic Editor: Kurt A. Jellinger

Received08 Dec 2011

Accepted31 Jan 2012

Published22 Jul 2012

Abstract

The world health organization (WHO) estimated that 18 million people are struck by Alzheimer's disease (AD). The USA, France, Germany, and other countries launched major programmes targeting the identification of risk factors, the improvement of caretaking, and fundamental research aiming to postpone the onset of AD. The glycogen synthase kinase 3 (GSK-3) is implicated in multiple cellular processes and has been linked to the pathogenesis of several diseases including diabetes mellitus, cancer, and AD. Inhibition of GSK-3 leads to neuroprotective effects, decreased β-amyloid production, and a reduction in tau hyperphosphorylation, which are all associated with AD. Various classes of small molecule GSK-3 inhibitors have been published in patents and original publications. Herein, we present a comprehensive summary of small molecules reported to interact with GSK-3. We illustrate the interactions of the inhibitors with the active site. Furthermore, we refer to the biological characterisation in terms of activity and selectivity for GSK-3, elucidate in vivo studies and pre-/clinical trials.

1. Introduction

Protein kinases regulate diverse cellular functions and thus are frequently exploited in drug discovery programmes [1]. They regulate signal transduction processes by phosphorylating serine, threonine and tyrosine residues in key proteins. The signalling pathways involved contribute to the pathology in many diseases [2, 3]. Glycogen synthase kinase 3 (GSK-3) was identified in the late 1970s and is a constitutively active, ubiquitous expressed serine/threonine kinase, which participates in a number of physiological processes ranging from glycogen metabolism to gene transcription [4]. Initially, the focus of pharmaceutical companies concerning GSK-3 was on diabetes mellitus, but since GSK-3 was linked to Alzheimer’s disease (AD), the focus has moved from diabetes to AD. GSK-3 has been linked to all primary abnormalities associated with AD. GSK-3 interacts with different components of the plaque producing amyloid system, participates in phosphorylating the microtubule binding protein tau that contributes to the formation of neurofibrillary tangles, and has an influence on presenilin and other AD-associated proteins [4–8]. Two related isoforms of GSK-3 are present in mammalians, GSK-3α and β, which share 98% homology in their catalytic domains and have similar biochemical properties [9]. The isoforms are similar in their catalytic domains, yet differ significantly in their N-terminal regions [10]. Alois Alzheimer’s first report of the neuropathological hallmarks of AD dates back to 1907 [11, 12]. The histopathology of the AD brain is characterized by the presence of abnormal filamentous tau-protein inclusions in nerve cells and extracellular amyloid deposits [13, 14]. Partially phosphorylated tau contains sequence motifs that support association with tubulin, which entails the stabilization of microtubules in AD-uneffected cells. The pathological hyperphosphorylation of these motifs destabilizes microtubules and consequently interferes with tubulin binding. The misfolding of hyperphosphorylated tau involves the E/Z-isomerisation of a phosphorylated Ser-Pro motive, which leads to the formation of insoluble neurofibrillary tangles (NFTs) and intraneuronal aggregates of paired helical filaments (PHFs) [9, 15]. GSK-3 phosphorylates multiple sites on tau both in vitro and in vivo [9]. It exerts a central and crucial role in the pathogenesis of both familial and sporadic forms of AD. Early-onset forms of familial Alzheimer’s disease (FAD) have been linked to mutations in amyloid precursor protein (APP), presenilin-1 (PS-1), and presenilin-2 (PS-2). These mutations adversely affect APP processing and result in the increased production of the 40–42 amino acid long β-Amyloid (Aβ) peptides, which are the major component of amyloid deposits. Several risk factors have been associated with sporadic Alzheimer’s disease (SAD). The most prevalent factors are aging and the presence of specific ApoE isoforms, which have been implicated in Aβ clearance. Sporadic Alzheimer’s disease can be caused by the activation of β-secretase, which results in enhanced formation of Aβ. Enhanced Aβ production or deficiency in Aβ clearance will result in the deposition of Aβ aggregates [4, 16]. Recent work suggests that enhanced GSK-3 activity increases Aβ production [17]. Several studies support that GSK-3 inhibition leads to decreased Aβ production and a reduction in tau hyperphosphorylation [1].

A plethora of GSK-3 inhibitors has been described, and most of the biological effects were reported for in vitro and cellular studies [17]. These studies, the number of patent applications, and a successful phase II trial indicate that GSK-3 is a promising drug target for AD therapy, but the ultimate proof of concept has not been presented yet. GSK-3 is highly enriched in the brain, and several publications indicate that the GSK-3β isoform is a key kinase required for abnormal hyperphosphorylation of tau [18, 19]. Spittaels et al. generated a double-transgenic mouse overexpressing human protein tau and constitutively active human GSK-3β and ascertained that this kinase is implicated in aberrant tau phosphorylation and in addition reduced tau binding capacity to microtubules [15, 20]. The homology of the ATP-binding pocket in GSK-3α and GSK-3β presents an obstacle for the development of isoform selective inhibitors. All GSK-3 inhibitors developed until now are able to inhibit the two isoforms with similar potency, except Λ–OS1 (36), which showed a selectivity (up to 7 fold) for GSK-3α [8, 21, 22].

The structures of GSK-3β cocrystallized with several inhibitors have been solved by X-ray crystallography recently. These structures provide a remarkable possibility to design both novel and selective GSK-3 inhibitors. There are two fundamental options to inhibit GSK-3: non-ATP competitive inhibition and ATP competitive inhibition.

The non-ATP competitive inhibitors, for example, substrate competitive inhibitors, usually engage in a weak-binding interaction with the enzyme [23]. Non-ATP competitive inhibitors do not compete with the high intracellular ATP-concentration and thus offer a distinct pharmacological advantage. Moreover, the involvement of GSK-3 in several essential signalling pathways imposes a limit on the GSK-3 inhibition, complete inhibition will result in adverse events.

Thus GSK-3 inhibitors suitable for AD therapy have to strike a balance between the different pathways. This delicate balance may be achieved by moderate inhibition in combination with excellent pharmacokinetics. Thiadiazolindiones (TDZDs) are non-ATP competitive GSK-3 inhibitors, which delivered a candidate for phase IIb trials recently [24]. The extended phase II trial (60-day treatment) did not reveal adverse effects [25]. However, the majority of the known GSK-3 inhibitors are ATP competitive and target the ATP binding pocket of GSK-3. Several small-molecule inhibitor/GSK-3 complexes can be extracted from the Protein Data Bank (PDB) (PDB codes: 3PUP (15), 1Q4L (25), 1Q3D (25), 1Q41 (25), 1Q3W (25), 1R0E (34), 2OW3 (40), 2JLD (55), 3M1S (56), 1UV5 (65), 3I4B (113), 3F7Z (119), 3F88 (119), 3GB2 (120), 1Q5K (124), 2O5K (127), 3L1S (130), 3Q3B (136), 1I09 (138)). A closer view at the interactions of these inhibitors with GSK-3 will be provided in the following sections.

2. Small-Molecule Inhibitors of Glycogen Synthase Kinase 3

Several ATP competitive GSK-3 inhibitors from different structural classes are highlighted in this paper. The in vitro and in vivo data are summarized if available. It should be noted that the IC₅₀ values strongly depend on assay conditions and thus may vary 100 fold depending on ATP and enzyme concentration as well as incubation time. The interactions between the inhibitors and the ATP binding pocket are depicted.

2.1. Lithium Chloride

Lithium chloride (LiCl) was the first GSK-3 inhibitor to be discovered. However, there are several other biological targets for lithium resulting in adverse events and a rather small therapeutic window. This effectively rules out the use of LiCl in the therapy of AD. The mechanism by which lithium inhibits GSK-3 is unknown, but two hypotheses were proposed: (a) lithium (Li⁺) is a competitive inhibitor of GSK-3 with respect to magnesium (Mg²⁺), but neither competitive to substrate nor to ATP (b) lithium inhibits potassium deprivation [25–27]. This paper focuses on small organic molecules that target specifically GSK-3, thus the activity of lithium salts will not be reviewed. Also covalent or irreversible inhibitors, like the TDZD NP-12, will be noted, but not further discussed as well as the FRATtide, a peptide derived from FRAT1, which binds to GSK-3 and blocks GSK-3 from interacting with axin [28, 29].

2.2. Maleimide Derivatives

Maleimide derivatives have been reported as scaffolds for ATP competitive GSK-3 inhibitors. Researchers at SmithKline Beecham Pharmaceuticals reported that 3-anilino-4-arylmaleimides 1–3 (Table 1) are potent and selective inhibitors of GSK-3 [30]. The compounds displayed GSK-3 inhibition (IC₅₀) at low nanomolar concentrations. The selectivity of compound 2 was evaluated using a panel of 25 kinases. The majority of the kinases showed less than 30% inhibition at an inhibitor concentration of 10 μM. The complex of 3 (named I-5) with GSK-3β (Figure 1) elucidated the binding mode to the ATP pocket [31]. Herein, the maleimide nitrogen interacts with the carbonyl oxygen of Asp133 and the oxygen of compound 3 with the backbone nitrogen of Val135. Two additional interactions are observed between a carboxylate oxygen and Arg141 and with Gln185. Compound 4 (SB-216763) inhibited GSK-3α with an IC₅₀ of 34 nM (Table 2). Derivative 4 exhibited little or no inhibition of the 24 kinases tested in the panel [32]. Incubation of cerebellar granule neurones with this compound reduced the death rate in a concentration-dependent manner in response to either stimulus. The maximal neuroprotection was observed with 3 μM of SB-216763 [33]. A 60% reduction in GSK-3β activity levels was observed in the hippocampus, but not in the cortex of SB-216763 treated animals versus vehicle-treated rats [34]. The compounds 5–11 revealed good potencies against GSK-3. Concerning compounds 7 and 9–11, much higher potencies (IC₅₀ < 4 nM) were ascertained in comparison to compound 1 (Table 2) [36–38]. The compounds 10 and 11 demonstrated very good GSK-3 inhibition and improved selectivity against PKCβII, CDK2, and CDK4 and inhibit tau phosphorylation in a neuronal cell line [38]. Whereas compound 12 was analyzed by in silico docking, the binding mode of 13 (IC₅₀ = 0.6 nM) was determined by X-ray crystallographic analysis (Figure 2) [40]. Similar to compound 3, the maleimide nitrogen of 13 interacts with the carbonyl oxygen of Asp133 and its oxygen with the backbone nitrogen of Val135. Furthermore, compound 13 forms a crucial hydrogen bond to Gln185. Maleimide 13 was screened against 317 kinases to provide data on kinase selectivity in order to predict potential safety issues. It was found that compound 13 inhibits only 36 kinases with >90% inhibition at 10 μM [40]. Compounds 14 and 15 are reversible GSK-3 inhibitors in the low micromolar or high nanomolar range and can be used as chemical precursors for the corresponding halomethylketones (HMKs). These HMKs are irreversible inhibitors, they alkylate Cys199, which is located in the ATP binding site of GSK-3 [41]. Further maleimide derivatives are listed in Table 3. All of them, compounds 16–27 showed IC₅₀/ values in the low nanomolar range [42–48]. The majority of these structures was synthesized by Johnson & Johnson Pharmaceutical R & D. The compounds 17 and 18 were evaluated against a broad panel of 55 protein kinases. 10 μM of derivative 17 or 18 inhibited GSK-3β kinase activity by 100% in the presence of 10 μM ATP. Compound 18 exhibited excellent selectivity for GSK-3β except for the moderate selectivity against PKCβII. Meanwhile, the bis-7-azaindolylmaleimide 17 exhibited high selectivity at GSK-3β against all kinases tested [43]. The activity of compound 23 was tested in a kinase panel containing 100 diverse protein kinases. An IC₅₀ of 3 nM and a 460 fold selectivity for GSK-3β over PKCβII was reported [46]. The X-ray structure analysis of cocrystallized compound 23 and GSK-3β is illustrated in Figure 3.

The maleimide establishes key hydrogen bond contacts with the residues Asp133 and Val135. The compounds 25 and 26 were docked into the ATP binding site of GSK-3β (PDB code 1R0E). Similar to other maleimide derivatives, the maleimide nitrogen interacts with the carbonyl oxygen of Asp133 and the oxygen with the backbone NH of Val135. In addition to these main interactions, the hydroxymethyl group of compound 26 interacts with the side chain of Arg141 [48].

The benzo[e]isoindole-1,3-dione 28 (Table 4) displays an IC₅₀ of 304 nM in the presence of 100 μM ATP. It was evaluated in a panel of 22 representative kinases. 5 μM of compound 28 inhibited 91% of GSK-3β activity as well as 71% of CDK2/cyclin A and 53% of KDR (VEGFR2) [49]. The inhibition of GSK-3 leads to ectopic activation of the Wnt pathway during zebrafish development, resulting in a headless embryo. Thus, zebrafish embryos, which were treated with compound 28, had highly restricted brain defects that ranged from smaller eyes and forebrain to a complete loss of these structures [49]. Compound 29 displayed a lower IC₅₀ in vitro than 30, whereas compound 30 displayed better in vivo efficacy. 25 μM of derivative 30 resulted in the eyeless phenotype of zebrafish embryos after 3 days of incubation [50]. The synthetic activity dedicated to this structural class has been strong and is ongoing [51–55].

2.3. Staurosporine and Organometallic Inhibitors

Staurosporine (31) is a natural product from the bacterium Streptomyces staurosporeus [56]. It exerts antimicrobial, hypotensive, and cytotoxic activity [57]. Staurosporine (31) is also a potent GSK-3β inhibitor with a reported IC₅₀ value of 15 nM (Table 5) [58]. The cocrystal structure of Staurosporine (31) with GSK-3β is elucidated in Figure 4. Again, the maleimide 31 interacts with the Asp133 carbonyl oxygen and the backbone nitrogen of Val135. These are the only direct hydrogen bonds observed between GSK-3β and this inhibitor [31]. The other polar interactions, for example, water-mediated interactions are not denoted. The organometallic ruthenium complex 32 is a remarkably potent inhibitor of GSK-3 (Table 5). The IC₅₀ for GSK-3α is 3 nM and 10 nM for GSK-3β. The compound was evaluated against 10 kinases and displayed activity against GSK-3 and RSK1 (IC₅₀ = 100 nM) only. The authors observed a water-mediated contact between the carbonyl ligand and the carbamide of Gln185 and assumed that this contributes to the specificity of GSK-3 [59]. Compound 33 showed improved selectivity. A test panel of more than 50 kinases was not significantly inhibited at 100 nM. Compound 33 was reported to activate the Wnt signaling pathway in cell culture experiments at nanomolar concentrations. The treatment of zebrafish embryos in early development by compound 33 caused malformations, for example, a head structure lacking the eyes and a stunted tail [60]. The S-diastereomer of compound 34 is a weaker GSK-3β inhibitor than the R-diastereomer: IC₅₀ of 0.22 nM at 100 μM. Compound 34 (R-diastereomer, Table 5) exerts the highest reported potency against GSK-3β with an IC₅₀ of 40 pM. Unfortunately, the evaluation in a kinase panel was not reported yet [61]. The complex of derivative 34 with GSK-3β (Figure 5) provided insight into the binding mode in the ATP pocket of GSK-3β. The interactions between the imide NH and the carbonyl oxygen of Asp133 and between the imide carbonyl and the NH of Val135 are typical. Another interaction is marked between the carbonyl oxygen of Val135 and the indolyl OH. The compound 34, and the analogues 35 ((R)-DW 12) and 36 (Λ-OS1) contain a carbonyl, which interacts with the flexible glycine-rich loop of GSK-3β (Figures 6 and 7). Thereby Ile62, Gly63, Phe67 and Val70 form a small hydrophobic pocket (Figure 6(b), compound 35). The structure activity analysis of ruthenium-based GSK-3 inhibitors lacking the carbonyl revealed the contribution of this carbonyl to potency and selectivity [22, 61, 62].

(a) Compound 35 in the ATP binding pocket of GSK-3β

(b) Rotated (a) to reveal the hydrophobic pocket containing Ile62, Phe67, Gly83, Val70, Lys85, and Glu97

2.4. Indole Derivatives

Several pharmaceutical companies have reported and patented indole derivatives as GSK-3 inhibitors [67–74]. Indirubins are likewise indole derivatives. They are related to the naturally occurring indigo dyes, and their pharmacological properties have long been known in traditional Chinese medicine, for example, in the treatment of leukemias [15]. Except for the dye indirubin 38, all other noted indole derivatives (37, 39–50) revealed an IC₅₀ below 100 nM. Compound 37, the indirubin-3′-monoxime, was reported to display an IC₅₀ of 22 nM on GSK-3 inhibition (Table 6). This unselective compound is a strong inhibitor of the closely related kinases CDK1 and CDK5 [58]. Compound 37 did not affect p-tau levels in neither cortex nor hippocampus of P12 rats despite the high concentration of the compound in the brain (13 μM) [34]. Three important interactions of compound 37 and GSK-3β are displayed in the X-ray in Figure 8 [31]. Maternal Wnt activity is necessary for dorsal axis formation in Xenopus laevis embryos, whereas head formation requires the inhibition of zygotic Wnt activity. The Xenopus laevis embryos were treated with compound 39 (BIO) or LiCl, respectively; in order to challenge these two GSK-3 regulated events in vivo. LiCl treatment leads to a hyper dorsoanteriorization at the expense of trunk and tail when applied during early cleavage stage. 39 exerted the same effect on the embryos. Compound 39 inhibited GSK-3 with an IC₅₀ of 5 nM, but also CDK1, CDK2, and CDK5 in a nanomolar range [63, 64]. The binding mode of 39 in the ATP pocket of GSK-3β has been determined by X-ray crystallographic analysis. The four major interactions between the inhibitor and GSK-3β are shown in Figure 9. The nitrogen interacts with the carbonyl oxygen of Asp133 and the oxygen with the backbone nitrogen of Val135. Moreover, interactions with the oxygens of Val135 and Pro136 as well as the van der Waals contact between the bromine and Leu132 were observed. Compounds 41 and 43 are potent GSK-3 inhibitors and very selective against CDK1/cyclin B and CDK5/p25 [64]. In 2007, this class of indirubine derivatives was patented by Meijer et al. [75]. This patent lists in vivo activity for several compounds. The derivatives 44–46 feature an extended amino side chain at position R¹. They were prepared to enhance selectivity and water solubility versus compound 39. These compounds were reported to inhibit β-catenin Ser33/37/Thr41 phosphorylation by GSK-3. Compounds 44–46 were also less cytotoxic than compound 39 in the MTS reduction assay of SH-SY5Y neuroblastoma cells [65]. The compounds 47–50 are potent, yet unselective GSK-3 inhibitors [66].

2.5. Paullone Derivatives

Paullones have been reported as potent ATP competitive inhibitors of CDKs and GSK-3β [76, 77]. Compounds 51–55 revealed that a defined derivatisation of one substituent only can increase the GSK-3β inhibition up to 155 fold. Alsterpaullone 55 (9-nitro-paullone) is one of the most potent GSK-3β inhibitors and competes with ATP for binding to GSK-3β (Table 7).

Compound 55 was evaluated in a kinase panel with 25 kinases and exhibited high selectivity for GSK-3α/β, CDK1/cyclin B, CDK2/cyclin A, CDK2/cyclin E, and CDK5/p35. All measured IC₅₀ values were in the nanomolar range. Alsterpaullone 55 was reported to inhibit the in vivo phosphorylation of tau at AD-specific sites by GSK-3β [76]. Paullone 55 formulated in 20% DMSO/25% Tween-80 and injected s.c. led to a reduction in 43 kDa tau phosphorylation in cortex after 2 h, though not in the 49 kDa isoform. Furthermore, the phosphorylation levels of the 43 kDa and 49 kDa isoforms in the hippocampus were significantly decreased [34]. Most of the paullone derivatives were patented by Meijer and Kunick in 2001 [81]. The binding mode of 55 has been determined by X-ray crystallographic analysis (Figure 10) [31]. The interactions of alsterpaullone and GSK-3β include two hydrogen bonds with Val135 and one interaction between the nitro group and the side chain amino group of Lys85. The compounds 56 and 57 inhibited GSK-3 as well as CDK1/cyclin B and CDK5/p25 in the nanomolar range [78]. The exchange of nitrogen and carbon in compound 58 and 59 decreased the inhibitory activity, but provided selectivity to 58, which is void of CDK-inhibitory effects [79]. However, compound 58 was tested against three kinases (GSK-3β, CDK1/cyclin B, and CDK5/p2) only. The derviatisation of the R² motif, see compounds 57 and 60–64 in Table 7, leads to the most potent inhibitor 64. Compound 64, with an IC₅₀ of 0.8 nM is likewise nonselective for GSK-3. It preferentially inhibited the CDK/GSK-3 family in the nanomolar range and VEGFR-2, VEGFR-3, and Src in the submicromolar range [80].

2.6. Pyrazolamide Derivatives

GlaxoSmithKline identified another class of GSK-3 inhibitors in 2003 (Table 8). The precursor was identified by a pharmacophore search of the in house database. The compounds 65–67 were profiled against a panel of 25 kinases including GSK-3β. An excellent selectivity was obtained against the majority of the kinases. However, a significant inhibition of CDK2/cyclin A was reported [82]. Compounds 68 and 69 displayed improved potency, but nevertheless inhibited CDK2/cyclin A. Only compound 70 showed an excellent GSK-3 potency and improved CDK-2/cyclin A selectivity [83]. The IC₅₀ comparison of compounds 71–73 revealed that the Ph-4-OH motif is the best. The most potent inhibitor 74 (IC₅₀ = 0.8 nM) was tested against a panel of kinases and showed a reduction in the overall selectivity profile [84, 85]. Compounds 75–77 showed an excellent selectivity against CDK-2/cyclin A. In addition, compound 77 demonstrated an excellent overall selectivity profile against all kinases of the panel [85]. Unfortunately, no further studies were published concerning this series.

Takeda Pharmaceutical disclosed compound 78 in 2009. It is a very potent inhibitor of GSK-3 with an IC₅₀ of 2.3 nM for GSK-3α and 2.0 nM for GSK-3β. It had no inhibitory effect on 23 kinases, and only a weak inhibition was detected for CDK1/cyclin B, CDK2/cyclin A, CDK5, and JNK1. The cold-water stress model (CWS) with male C57BL/6Njcl mice was used to evaluate the in vivo efficacy of compound 78. CWS transiently induces in vivo tau hyperphosphorylation as reported in previous studies. The compound displayed highly potent inhibition of in vivo phosphorylation in CWS mice and reduced sarkosyl insoluble tau in old homozygous JNPL3 mice. Furthermore, compound 78 inhibited tau phosphorylation at GSK-3-directed sites in rat primary neuronal cells and mouse brain tissue [86]. Several structures containing a pyrazole core have shown promising results in animal models of diabetes, for structural information see denoted references.

The pyrazolamides developed by Wyeth-Ayerst Research, now Pfizer, showed significant plasma glucose-lowering activity (16–42% reduction) in genetically obese, diabetic db/db mice [87, 88]. Novartis published a series of compounds with ED₅₀ values for glucose reduction in ob/ob mice of 3.0 mg/kg/day [89]. In 2011, the Merck Research Laboratories disclosed a potent human glucagon receptor antagonist with good pharmacokinetic profiles in four preclinical species. One of these compounds showed excellent oral pharmacodynamic efficacy in rhesus monkeys and transgenic mice by blocking glucagon-induced hyperglycemia [90].

2.7. Pyrimidine and Furopyrimidine Derivatives

GSK-3 inhibitors bearing the pyrimidine moiety are listed in Tables 9 and 10. This series is characterized by a high number of patent applications, particularly by Vertex Pharmaceuticals [97–122]. Compounds 79 and 81 inhibited GSK-3β in the nanomolar range. The in silico docking of compound 80 into the ATP binding pocket of GSK-3β suggested that 80 makes two hydrogen bonds with the hinge region and one interaction with the positively charged Arg141 [28, 91]. Unfortunately, the activity of these compounds in a kinase panel was not disclosed. The compounds 82–90 are weak inhibitors of GSK-3, and there are no public data for in vivo activity nor selectivity. Docking of 90 into the PDB structure 1Q5K of GSK-3β suggested that one nitrogen and the secondary amine form hydrogen bonds to the hinge region at the Val135 NH and carbonyl, respectively. The following compounds 91–93 showed IC₅₀ values below 100 nM, but 91 and 92 inhibit Aurora A in the nanomolar range. Derivative 93 (GSK-3α IC₅₀ = 61 nM, GSK-3β IC₅₀ = 41 nM) inhibited Aurora A at micromolar concentration only. In vivo studies of this compound in rats showed 34% oral bioavailability and good exposure [92]. Compound 94, a lead compound for ERK2 inhibition, is a nonselective GSK-3 inhibitor and inhibited all 5 kinases in the panel, which included GSK-3 [93]. The complex of compound 94 with GSK-3β (Figure 11) provided the binding mode in the ATP pocket of GSK-3. The secondary amine interacts with the carbonyl oxygen of Val135 and the nitrogen of compound 94 with the backbone NH of Val135. Two additional interactions are present between OH and Asp200 and between the carbonyl and the primary amine of Lys85. The arylimidazoles 95 (CHIR 99021) and 96 (CHIR 98014) are very effective ATP competitive inhibitors of murine and rat GSK-3 (IC₅₀ ≤ 10 nM). Both compounds exhibited 500 to 10000 fold selectivity for GSK-3 versus 20 other kinases tested. These GSK-3 inhibitors rapidly lower blood glucose levels in diabetic rodent models and enhance glucose transport as well as GS activation in insulin-resistant oxidative skeletal muscle from type 2 diabetic rats [94]. The nitropyridine 96 exerts a very potent reduction of Ser396 tau phosphorylation in a human neuronal cell line. P12 rats were injected i.v. with 30 mg/kg of CHIR 98014 (96, dissolved in DMSO) to test the efficacy on tau phosphorylation in vivo, resulting in a maximal brain concentration of 7 μM. Tissue analysis by Western blotting using a p-tau Ser396 antibody showed approximately 40% reduction in the phosphorylation of 43 kDa and 49 kDa tau in the cortex and a significant 3 fold reduction of the 43 kDa isoform in the hippocampus. Moreover, a 50% reduction of GSK-3β activity was observed in compound 96 treated animals versus vehicle [34].

The denoted furopyrimidines 97–102 inhibited GSK-3β with an IC₅₀ below 40 nM (Table 10). Compound 100 (GSK-3β IC₅₀ = 5 nM) displayed excellent selectivity against 25 kinases, including CDK2/cyclin A, which was inhibited with an IC₅₀ of 0.46 μM. Compound 100 was examined in a glycogen accumulation assay in L6 cells and exhibited excellent induction of glycogen accumulation (EC₅₀ = 0.39 μM) [95]. Compound 101 was also profiled by cross-screening against a variety of kinases and showed an excellent overall selectivity against all kinases tested including CDK2. The docking of 101 into the ATP binding site of GSK-3β provided a likely interaction. One nitrogen and NH₂ of aminopyrimidine are anchored to the carbonyl moiety and NH of Val135 via hydrogen bond interactions. The 3-pyridine moiety is located close to Lys85 of the conserved salt bridge (Lys85/Glu97). The EC₅₀ value of compound 101 in the glycogen accumulation assay in L6 cells was 3.2 μM and thus 9 fold higher than for compound 100 [96].

2.8. Oxadiazole Derivatives

Tables 11–13 list GSK-3 inhibitors featuring the oxadiazole moiety. The depicted 1,2,5-oxadiazoles, 103–109, revealed IC₅₀ values from 0.1 μM to more than 1.1 μM. Compounds 104–106 were screened for inhibitory activity against a panel of 32 kinases at 100 μM ATP concentration. All compounds gave at least 100 fold selectivity for GSK-3 compared to CDK2. However, 10 μM of compound 104 inhibited other kinases like MSK1 and DYRK1A, the latter activity is of interest for neurodegenerative diseases. The above mentioned compounds 104–106 displayed both sufficient cell penetration and suitable water solubility [123]. The dioxolane 110 was identified as GSK-3β inhibitor (IC₅₀ = 65 nM; Table 12) by high throughput screening. The X-ray analysis of the GSK-3β cocrystallized compound confirmed the interaction with the ATP binding site (Figure 12). One oxygen and a neighbouring hydrogen atom of the benzodioxole establish hydrogen bonds with the amide NH hydrogen and carbonyl oxygen of Val135 in the hinge region. The nitrogen atoms of the oxadiazole engage in an unique hydrogen bond relay network between Lys85-Glu97-Asp200 via two water molecules (interactions not shown). Further interactions are denoted in Figure 12. After an extensive derivatisation, for example, 111–114, compound 114 (Figure 13) exerts a 28 fold increased activity (GSK-3β IC₅₀ = 2.3 nM) compared to its homologue 110 (Table 12). The selectivity of 114 was evaluated in a panel of more than 20 kinases to reveal more than 1000 fold selectivity against CDK1, CDK2, and CDK5. In addition, rat cassette dosing experiments of compound 114 were performed, which revealed low oral bioavailability. The cocrystal structure of 114 bound to GSK-3β was not fully characterized due to the cleavage of the S–C bond in the X-ray beam (Figure 13) [125]. The cocrystal structure indicated that the nitrogen of the benzimidazole forms a hydrogen bond with the backbone NH of the hinge region at Val135, and one nitrogen of the oxadiazole ring makes a hydrogen bond with the NH of Asp200. The hydrogen atom on the carbon of the benzimidazole made an additional hydrogen bond with the carbonyl oxygen of Val135 [125]. The compounds 115 and 116 are enantiomers just as compounds 117 and 118. The S-isomers 116 and 118 were found to be eutomers. It was reported that the S-isomers possessed good oral absorption in nonfasted Crl: CD(SD)IGS rats with a bioavailability of 72.8% for derivative 116 and 65.5% for derivative 118. Furthermore, the compounds exhibited favourable blood-brain barrier (BBB) permeability. Compounds 116 and 118 were tested for inhibitory activity against more than 20 kinases and displayed no significant activity. This indicates that these compounds are highly selective GSK-3 inhibitors. The binding mode of 116 in the ATP pocket of GSK-3β has been determined by X-ray crystallographic analysis (Figure 14) [126]. One of the nitrogen atoms of the oxadiazole was revealed to interact via a hydrogen bond with the side chain of Lys85 and the other with Asp200. The oxygen atom and one carbon hydrogen of the benzofuran ring interact with the main chain of Val135. Another interaction was observed between one carbon hydrogen and the carbonyl of Asp133. Derivatives 116 and 118 were tested in vivo using the CWS model in mice. Here, tau phosphorylation was induced at several GSK-3β-directed sites such as Ser199, Thr205, Thr231, and Ser396 in mice. As reported, tau phosphorylation was significantly reduced by 35% for compound 116 and 38% for compound 118 [126]. Compound 116 was further investigated and revealed significantly decreased hippocampal tau phosphorylation as well as suppression of tau pathology without affecting amyloid β pathology [127].

A multistage virtual screening of 289903 molecules resulted in 59 hits of potential GSK-3β inhibitors, for example, compound 119. Biological tests confirmed the IC₅₀ of 17 nM and good selectivity versus CDK2. It crosses the BBB and has a good hepatic glycogen effect in mice. The derivatisation, for example, 120–122, of compound 119 lead to compound 122 with an IC₅₀ of 7 nM. Surprisingly, docking experiments of compound 122 revealed a different binding mode in comparison to the cocrystallized oxadiazoles 110, 114 and 116. The in silico docked oxadiazole motif coordinates to the GSK-3β hinge region, Val135, Tyr134, and Asp133, instead of binding to the polar region, Lys85, Cys199, and Asp200 [128].

The last denoted oxadiazoles are the 1,2,4-oxadiazoles 123–127, which exert moderate inhibition of GSK-3β only (Table 13). A subset of these oxadiazoles (123–125) exhibited weak inhibition of Pim-1 and no detectable inhibition towards seven other kinases tested at 10 μM concentration [129].

2.9. Thiazole Derivatives

The benzothiazoles 128 and 129 (Table 14) are nonselective GSK-3 inhibitors and showed moderate activity against CDKs [130]. This stands in contrast to the thiazolylurea 130 (AR-A014418), which strongly inhibited GSK-3 (IC₅₀ = 104 nM) but not any other kinase in the panel. AR-A014418 inhibited tau phosphorylation in transfected 3T3-fibroblasts in a dose-dependent fashion exhibiting an IC₅₀ of 2.7 μM. The neuronal loss was reduced in the organotypic culture (N2A cells) and compound 130 by itself did not affect neuronal viability. The cocrystal structure analysis of AR-A014418 and GSK-3β revealed that this compound binds to the hinge region via three hydrogen bond interactions (Figure 15) [131]. Furthermore, compound 130 significantly reduced insoluble tau levels in the brainstem of JNPL3 mice when compared with vehicle treated animals [132]. Surprisingly, another research group reported that AR-A014418 showed no effect on the phosphorylation levels of neither 43 kDa nor 49 kDa tau in the cortex or hippocampus of postnatal model rats [34]. Novel compounds based on the scaffold of AR-A014418 were synthesized recently. They showed improved in vitro activity and reduced toxicity in the wildtype zebrafish embryo assay [133].

2.10. Miscellaneous Heterocyclic Derivatives with GSK-3 Activity

Table 15 lists GSK-3 inhibitors featuring a benzimidazole core. There are neither in vivo assays nor selectivity data published for these potential metal chelators 131–134 (Table 15(a)). However, compound 134 (GSK-3β IC₅₀ = 15 nM) was cocrystallized with GSK-3β (Figure 16) [134].

Herein, the secondary amine interacts with the carbonyl oxygen of Val135 and the phenolic OH of 134 with the carbonyl of Asp133. Two more interactions are established between the SO₂ of compound 134 and the arginines Arg141 and Arg220. The 1-aza-9-oxafluorenes 135–137 are moderately active GSK-3β inhibitors, but showed activity for CDKs (Table 15(a)) [135].

There is no report for an in vitro IC₅₀ of the synthetic xanthine propentofylline (PPF, compound 138, Table 15(a)), but studies in the Tg mouse model of AD indicated that PPF exerts a dual effect: reduction of both pathological amyloidogenesis and tau phosphorylation while reducing the ratio of activated versus inactivated GSK-3β [136].

The pyrazolone 139 was identified as potential scaffold in a compound screen for novel GSK-3 inhibitors. Derivatisation has increased the potency of the derivatives ( from 1.49 mM to 0.8 nM (Table 15(b)). The compounds 140, 141, and 143 showed selectivity in a kinase panel of 14 kinases. A cocrystallization was realized with compound 142 (Figure 17) and provided the interactions of the pyrazole moiety with the GSK-3 backbone aminoacids Asp133 and Val135. In addition, the methoxy substituents make hydrogen-bonding contacts with both Asp200 and Lys85. These interactions and the hydrophobic contacts of the phenyl rings are thought to be responsible for the potency and selectivity [137]. A recent docking study of the pyrazolone 144 confirmed the interactions of compound 142 with GSK-3β. It is an active (IC₅₀ of 34 nM) and selective (kinase panel of 40 kinases) structural analogue to the previously described maleimides 9–27 (Tables 2 and 3). Furthermore, compound 144 was evaluated in a model of oxidative stress induced by homocysteic acid and displayed full neuroprotective activity at 1 μM. Additionally, it was able to reduce locomotor activity in the chlordiazepoxide/amphetamine-induced hyperactivity model in vivo [138]. The compounds 145–147 are moderate GSK-3 inhibitors and were not tested against other kinases to evaluate their selectivity (Table 15(b)). Compound 145 increased the glycogen content in the liver of Sprague-Dawley rats in a dose-dependent manner [139].

Compound 1 is a HTS hit, which was cocrystallized with GSK-3β and solved by X-ray crystallography (Figure 18). The overlap of the inhibitor Compound 1 with a pyridone derivative revealed interactions with the catalytic triad, especially Lys85, and the protein backbone aminoacid Val135 of GSK-3β [140]. This leads to the latest ATP competitive GSK-3 inhibitors, the pyridones 148–150 (Table 15(b)). Compound 150 revealed potent in vitro inhibition with an IC₅₀ of 16.1 nM against GSK-3β. It was selective in a broad panel of kinases, including CK2 and CLK1. Compared to compound 148, compound 150 exhibited an improved in vitro human liver microsome intrinsic clearance value of 16.3 mL/min/kg. The in vivo CNS penetration assay demonstrated a good free brain to free plasma ratio and the assessment of potential genetic toxicology hazards was negative for compound 150 [140]. Last but not least, there were several GSK-3 inhibitors isolated from marine organisms. These alkaloids have the potential to provide new scaffolds comparable to the established indirubines. Manzamines, meridianins, hymenialdisine and dibromocantharelline inhibit GSK-3β in the μM range and display promising selectivity and in vivo results (Table 15(c); compounds 151–154) [141–144].

3. Activity and Selectivity Profiling

A plethora of GSK-3 inhibitors was discovered in recent years, and most of these displayed good-to-excellent inhibition of this kinase. However, selectivity and safety against other kinases remains to be a challenge. The structural analysis of the ATP competitive inhibitors may guide the development of more selective GSK-3 inhibitors. All ATP competitive inhibitors establish hydrogen bonds with the backbone atoms of Asp133 and Val135. Contact to these aminoacids is a key to enhance affinity to GSK-3, but it does not provide selectivity over other kinases. Moreover, Pro136 appears in several complexes to strengthen the interaction of the inhibitor with the backbone (Figure 19). One region of GSK-3 may offer privileged access to enhanced activity and selectivity: it is the region characterized by the aminoacids Lys85, Glu97, and Asp200. Lys85 was observed to form a salt-bridge with Glu97 and simultaneously with Asp200, which is expected to be less significant and potent as the one with Glu97 [145]. The interaction of an inhibitor with this region holds potential to increase activity and selectivity for GSK-3. This interaction can be mediated via water molecules, as observed for AR-A014418 (130), or be established by direct contact. We observed in our dataset that a direct interaction with this region may cause a loss of selectivity (data not shown). There is a salt-bridge formed by Glu137 and Arg141 in the entrance area of the ATP pocket of GSK-3β. This region seems to contribute to the activity and selectivity of several inhibitors.

Another important interaction between GSK-3 and an organometallic inhibitor was reported by Bregman et al. They observed a water-mediated contact between the carbonyl ligand of the inhibitor and the carboxylate of Gln185 [59]. This water molecule was also found in other GSK-3β inhibitor complexes and seems to be responsible for an increased activity and especially for an improved selectivity towards GSK-3.

Docking studies with our inhibitors confirmed this interaction and further explained the selectivity of these inhibitors (data not shown). Feng et al. observed that the ruthenium-coordinated CO ligand of their inhibitor interacts with the flexible glycine-rich loop formed by Ile62, Gly63, Phe67, and Val70. This pocket, which is not shown in Figure 18, seems to be crucial for potency and selectivity [22]. Figure 18 illustrates in a simple scheme how to enhance activity and selectivity of inhibitors. The interaction with at least two of the three areas deems necessary to provide active and selective inhibitors.

4. Examples of In Vivo Tests

Over the last decade, several animal models have been developed to study tauopathies and other neurodegenerative disorders in vivo. Despite some obvious advantages of the diverse AD invertebrate systems, the vertebrate animal models of AD are generally favoured (for detailed invertebrate reviews, see [147–149]). Vertebrate models are evolutionary and morphologically closer related to humans, which makes the direct translation of experimental results easier and more reliable. A conditionally GSK-3β overexpressing mouse was reported by Lucas et al. in 2001. They demonstrated that GSK-3β overexpressed in vivo results in neurodegeneration and proposed that these mice can be used to study some aspects of AD [150]. In 2005, Perez et al. and Ribe et al. developed and characterized a double-transgenic mouse line based on overexpression of human mutant APP and tau [151, 152]. They treated this transgenic mouse model with NP12, a non-ATP competitive GSK-3β inhibitor, and observed lower levels of tau phosphorylation, decreased amyloid deposition and prevention of memory deficits [18]. The APP-V7171 × Tau-P301L mice with combined amyloid and tau pathology and the GSK-3β × Tau-P301L mice with tauopathy only were reported by Terwel et al. in 2008. These models offer the possibility to explore molecular signals that act upstream and downstream of, or in parallel with GSK-3 isozymes [153]. Two transgenic mice models were developed to study the interaction between APP or Aβ and tau: the triple-transgenic model (3 × Tg-AD) harboring , APP_Swe and transgenes and the TAPP mice [154, 155].

The transgenic mice have been the major species used for modelling AD and frontotemporal dementia (FTD). JNPL3 mice are well-characterized transgenic mice that express human 4R0N tau with a FTDP-17 (P301L) mutation [156]. In particular, the levels of sarkosyl insoluble tau in JNPL3 mice increase in an age-dependent manner and comigrate with insoluble tau from AD and FTDP-17 brains. Thus, treatment with GSK-3 inhibitors should result in a significant reduction of sarkosyl insoluble tau, see, for example, compound 78 [86, 132]. Besides JNPL3 mice, the transgenic zebrafish larvae have advanced as an AD model system. It combines many of the advantages of invertebrate and vertebrate models. The latest model is a Gal4/UAS-based vector system that efficiently generates transgenic zebrafish overexpressing high levels of human Tau-P301L or other disease-associated proteins. This tau-transgenic fish model could be an effective in vivo screening tool to identify quickly promising GSK-3 inhibitors and eliminate compounds without reasonable in vivo activity early in the screening process [157, 158].

GSK-3 inhibitors have also specific effects on early wildtype zebrafish development when treatment occurs between 4 and 24 hpf. Thus this animal model can be used to test the efficacy of GSK-3 inhibitors in vivo [133, 157]. Furthermore, there are two in vivo model systems with transiently induced tau hyperphosphorylation that were used to evaluate the activity of GSK-3 inhibitors. One of them is the cold-water stress (CWS) model, which causes a rapid and reversible enhancement of tau phosphorylation in the mouse brain at several GSK-3β directed sites such as pSer199, pThr205, pThr231, and pSer396 [125, 159]. The CWS-model proves the significant reduction of tau phosphorylation in LiCl- or compound 78-treated mice [86, 160]. The in vivo activities of several other GSK-3 inhibitors (e.g., compound 55 and 96) were demonstrated in the postnatal rat model [34]. This in vivo model takes advantage of the well-characterized GSK-3β expression level in the early and later life cycle of rats [161, 162].

5. Compounds in Preclinical and Clinical Trials

Currently, several GSK-3 inhibitors pass through preclinical or clinical trials. Subsequently GSK-3 inhibitors are listed with the therapeutic indication of AD. These examples are taken from the database of PharmaProjects by searching for the criteria GSK-3 and Alzheimer (March 2010), the MED-D report of GESENT (May 2009) and ClinicalTrials.gov (August 2011).

The Wayne State University is currently in phase IV with lithium carbonate against bipolar disorder whereas the University of Sao Paulo is in phase II with lithium carbonate against GSK-3 for AD and cognitive impairment. Lithium against AD was submitted by the National Institute of Neurological Disorder and Stroke and is in phase II, but there was no update since March 2008. Two compounds from Noscira, NP-12 (TDZD) and NP-103, are in the pre-/clinical trials. NP-12 (NP031112, tideglusib) is currently in a phase IIb clinical trial for AD. At the moment, NP-103 and CG-301338 from CrystalGenomics and an GSK-3β inhibitor from Takeda are in preclinical trials. The development status of XD-4241 from Cambrex, SB-415286 from GlaxoSmith-Kline, a GSK-3β inhibitor from Amphora, SAR-502250 from Sanofi-Aventis, CEP-16805 from Cephalon, and an GSK-3β inhibitor from Lundbeck are not reported. The failure or progress of these compounds into preclinical and clinical trials will stimulate or discourage further research.

6. Summary

The moderate inhibition of GSK-3 by selective inhibitors with excellent pharmacokinetic properties and excellent blood-brain barrier permeation holds high potential for the treatment of AD. The failure of the first potent GSK-3 inhibitor by Astra-Zeneca indicates the complexity of this target and the therapeutic window of GSK-3 inhibition in adult mammals. Information on the failure is rather limited, it may be due to potential toxicity of the chemical scaffold: P450-mediated metabolism of thiazoles has resulted in hepatotoxicity and thus failure of phase III candidates previously.

Biological characterization has advanced GSK-3 as a potential drug target, and the inhibition of this protein kinase by small molecules resulted in significant inhibition of tau phosphorylation. We have described a wide range of molecules that inhibit GSK-3 and discussed their properties. We focused on several inhibitors interacting with the ATP binding pocket of GSK-3β. The water molecule interactions are not incorporated in the figures; however, they may play a crucial role in the hydrogen bond network between the inhibitor and the aminoacids. The aminoacids, which are responsible for strong interaction with the enzyme, have been identified. Noteworthy are Asp133, Val135, Glu137, Arg141, Gln185, Asp200, and Arg220, which constitute important aminoacids for interactions with the binding pocket of GSK-3. The conserved salt bridge Lys85/Glu97 materializes as an interesting interaction partner. We summarized crucial biological findings and provided an overview on the in vivo effects of some inhibitors. Additional in vivo assays can be retrieved via the references denoted in the tables next to the structures. We summarized the GSK-3 inhibitors, which are in pre-/clinical trials with the therapeutic indication of AD. Yet, a review will be biased, and we request your pardon or input, if your favourite inhibitor or in vivo studies are not adequately referred to.

7. Outlook

GSK-3 is an intriguing enzyme, which plays important roles in the pathogenesis of several diseases, for example, diabetes, cancer, and AD. The literature is immense and quite often provides conflicting statements and observations for this kinase. For example, a few studies observed that Pin1 (peptidyl-prolyl cis-trans isomerase) knockout mice display tau hyperphosphorylation and that this enzyme might have an inhibitive role in phosphorylating tau and GSK-3β, thus protecting against AD [163]. Whereas another study ascertained that the GSK-3 inhibitor BIO (compound 39) may be useful in regenerative medicine, by reversibly maintaining human embryonic stem cells in an undifferentiated state [164]. A plethora of GSK-3 inhibitors has been published since it has been linked to AD. Naturally, the vast majority thereof was reported by pharmaceutical companies. Many potent inhibitors with good selectivity have been disclosed so far. The challenge of medicinal chemists will be to develop inhibitors, which translate their potent enzymatic inhibition into cellular settings and finally humans, who will tolerate a moderate GSK-3 inhibition only. A mild GSK-3 inhibition (~35%) is needed because such an inhibition level provides sufficient insulin sensitization without elevation of β-catenin levels. Thus a moderate inhibition minimizes significant mechanism-based toxicities, ranging from hypoglycemia to tumorigenesis [165, 166]. A further indication of a moderate GSK-3 inhibition is the application of lithium for the treatment of bipolar disorder. The GSK-3 inhibitor lithium is estimated to inhibit approximately 25% of total GSK-3 activity. It was used for the treatment of bipolar disorder since the 1950s without association of hypoglycemia, increased levels of tumorigenesis, or deaths from cancer [167]. Nevertheless, the established in vivo studies have to be accompanied by the investigation of pleiotropic activity and the determination of a safe therapeutic window for chronic GSK-3 inhibition in humans. The X-ray analysis of cocrystallized structures revealed how the inhibitors interact with the ATP-binding pocket and provide information about essential interaction partners to improve potency and selectivity. The comparison of the IC₅₀ values will be much easier, if only one stringent GSK-3 in vitro assay would be utilized, which employs a defined final ATP and inhibitor concentration as well as a standardized incubation time. Currently, Alon et al. determined that GSK-3β is responsible for the phosphorylation of the embryonic tau isoforms in birds, which harbors the GSK-3β gene only. In consideration of their and former studies, Alon et al. assume that GSK-3α and β have distinct roles in phosphorylating tau in adult and embryonic brain in nonvertebrates. Furthermore, they raise the hypothesis that specific inhibition of GSK-3α may be useful for therapeutic intervention in AD [168]. This supposition is enhanced by former siRNA experiments [169]. But all GSK-3 inhibitors developed until now inhibit the two isoforms of GSK-3 equipotently, except Λ-OS1 (36) (~7 fold more selective for GSK-3α). Still most of the GSK-3 inhibitors fail in model animals despite of their good inhibitory activity in cell free assays. This is frequently due to the lack of selectivity, insufficient cell permeation, and poor blood-brain barrier permeability. Appropriate animal models were developed in transparent zebrafish to study preclinical efficacy, metabolic stability and toxicity, but their potential is not fully exploited. These in vivo tests are fast (3 days), relatively inexpensive and suitable for larger screening efforts in 96-well format. Furthermore, it has been observed that resistance arises during the therapy. The problem is that most of the kinase inhibitors are ATP competitive type I inhibitors. A new generation of type II inhibitors, which binds to the ATP site and extends into an allosteric site, may provide a solution [15, 170, 171]. Such novel type II inhibitors must be active, selective and permeate the human blood-brain barrier, which bears further limitations for drug development. However, several pharmaceutical companies continue to develop ATP competitive GSK-3 inhibitors [172, 173]. Just a few pharmaceutical companies have started pre-/clinical trials addressing the druggability of GSK-3 inhibition. Noscira launched the phase IIb trial ARGO of Tideglusib (NP-12) to treat mild-to-moderate AD patients in April 2011. The trial period will be 65 weeks with 2 dosage regimes of Tideglusib (500 and 1000 mg/day oral suspension, ClinicalTrials.gov identifier: NCT01350362). The ongoing clinical trials may lead to a paradigm shift, if the GSK-3 inhibitors display efficacy and safety.

Abbreviations

Å:	Angstrom
AD:	Alzheimer’s disease
ApoE:	Apolipoprotein E
APP:	Amyloid precursor protein
Arg:	Arginine
Asp:	Aspartic acid
ATP:	Adenosine triphosphate
Aβ:	β-Amyloid
BBB:	Blood-brain barrier
CDK:	Cyclin-dependent kinase
CK2:	Casein kinase 2
CLK1:	Dual specificity protein kinase 1
CWS:	Cold-water stress
Cys:	Cysteine
DMSO:	Dimethyl sulfoxide
DYRK1A:	Dual specificity tyrosine phosphorylation-regulated kinase 1A
EC50:	Half maximal effective concentration
ERK:	Extracellular signal-regulated kinase
FAD:	Familial Alzheimer’s disease
FTD:	Frontotemporal dementia
GESENT:	Gesellschaft für experimentelle und klinische Neurotherapeutika
Gln:	Glutamine
Glu:	Glutamic acid
Gly:	Glycine
GS:	Glycogen synthase
GSK-3:	Glycogen synthase kinase 3
h:	hour
HMK:	Halomethylketone
i.v.:	Intravenous
IC50:	Half maximal inhibitory concentration
Ile:	Isoleucine
JNK:	c-Jun N-terminal kinase
kDa:	kilodalton
KDR:	Kinase insert domain receptor
kg:	kilogram
:	Dissociation constant for the inhibitor
Leu:	Leucine
LiCl:	Lithium chloride
Lys:	Lysine
MED-D:	Medikamentenentwicklung für Demenzen in Deutschland
mg:	milligram
MSK1:	Mitogen- and stress-activated protein kinase
MTS:	3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxy-methoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium
μM:	micromolar
NFTs:	Neurofibrillary tangles
nM:	nanomolar
PDB:	Protein Data Bank
Phe:	Phenylalanine
PHFs:	Paired helical filaments
Pim-1:	Proto-oncogene serine/threonine-Protein kinase
Pin1:	Peptidyl-prolyl cis-trans isomerase
PKCβII:	Protein kinase C βII
PPF:	Propentofylline
Pro:	Proline
PS-1/2:	Presenilin-1/2
pSer:	phosphorylated Serine
pThr:	phosphorylated Threonine
RSK1:	Ribosomal protein S6 kinase alpha-1, also known as RPS6KA1
s.c.:	Subcutane
SAD:	Sporadic Alzheimer’s disease
Ser:	Serine
Src:	Proto-oncogene tyrosine-protein kinase
TDZD:	Thiadiazolidine
Thr:	Threonine
Tyr:	Tyrosine
Val:	Valine
VEGFR:	Vascular endothelial growth factor receptor
WHO:	World health organization
Wnt:	Signaling pathway
X-ray:	X-radiation.

References

L. K. Chico, L. J. van Eldik, and D. M. Watterson, “Targeting protein kinases in central nervous system disorders,” Nature Reviews Drug Discovery, vol. 8, no. 11, pp. 892–909, 2009.
View at: Publisher Site | Google Scholar
D. Bossemeyer, “Protein kinases—structure and function,” The FEBS Letters, vol. 369, no. 1, pp. 57–61, 1995.
View at: Publisher Site | Google Scholar
C. Peifer and D. R. Alessi, “Small-molecule inhibitors of PDK1,” ChemMedChem, vol. 3, no. 12, pp. 1810–1838, 2008.
View at: Publisher Site | Google Scholar
C. Hooper, R. Killick, and S. Lovestone, “The GSK3 hypothesis of Alzheimer's disease,” Journal of Neurochemistry, vol. 104, no. 6, pp. 1433–1439, 2008.
View at: Publisher Site | Google Scholar
I. Ferrer, T. Gomez-Isla, B. Puig et al., “Current advances on different kinases involved in tau phosphorylation, and implications in Alzheimer's disease and tauopathies,” Current Alzheimer Research, vol. 2, no. 1, pp. 3–18, 2005.
View at: Publisher Site | Google Scholar
F. Hernandez, E. Gomez de Barreda, A. Fuster-Matanzo, J. J. Lucas, and J. Avila, “GSK3: a possible link between beta amyloid peptide and tau protein,” Experimental Neurology, vol. 223, no. 2, pp. 322–325, 2010.
View at: Publisher Site | Google Scholar
A. Leroy, I. Landrieu, I. Huvent et al., “Spectroscopic studies of GSKβ phosphorylation of the neuronal tau protein and its interaction with the N-terminal domain of apolipoprotein E,” The Journal of Biological Chemistry, vol. 285, no. 43, pp. 33435–33444, 2010.
View at: Publisher Site | Google Scholar
A. Martinez, A. Castro, I. Dorronsoro, and M. Alonso, “Glycogen synthase kinase-3 (GSK-3) inhibitors as new promising drugs for diabetes, neurodegeneration, cancer, and inflammation,” Medicinal Research Reviews, vol. 22, no. 4, pp. 373–384, 2002.
View at: Publisher Site | Google Scholar
H. Eldar-Finkelman, “Glycogen synthase kinase-3: an emerging therapeutic target,” Trends in Molecular Medicine, vol. 8, no. 3, pp. 126–132, 2002.
View at: Publisher Site | Google Scholar
S. Frame and P. Cohen, “GSK3 takes centre stage more than 20 years after its discovery,” Biochemical Journal, vol. 359, no. 1, pp. 1–16, 2001.
View at: Publisher Site | Google Scholar
A. Alzheimer, “Über eine eigenartige Erkrankung der Hirnrinde,” Allgemeine Zeitschrift für Psychiatrie und psychisch-gerichtiliche Medizin, vol. 64, pp. 146–148, 1907.
View at: Google Scholar
R. A. Stelzmann, H. N. Schnitzlein, and F. R. Murtagh, “An English translation of Alzheimer's 1907 paper, 'uber eine eigenartige erkankung der hirnrinde',” Clinical Anatomy, vol. 8, no. 6, pp. 429–431, 1995.
View at: Publisher Site | Google Scholar
D. Dickson, Weller R. O. et al., Neurodegeneration: The Molecular Pathology of Dementia and Movement Disorders, Wiley-Blackwell, 2nd edition, 2011.
C. Duyckaerts, B. Delatour, and M. C. Potier, “Classification and basic pathology of Alzheimer disease,” Acta Neuropathologica, vol. 118, no. 1, pp. 5–36, 2009.
View at: Publisher Site | Google Scholar
M. P. Mazanetz and P. M. Fischer, “Untangling tau hyperphosphorylation in drug design for neurodegenerative diseases,” Nature Reviews Drug Discovery, vol. 6, no. 6, pp. 464–479, 2007.
View at: Publisher Site | Google Scholar
F. Hernández and J. Avila, “The role of glycogen synthase kinase-3 in the early stages of Alzheimers' disease,” The FEBS Letters, vol. 582, no. 28, pp. 3848–3854, 2008.
View at: Publisher Site | Google Scholar
P. Cohen and M. Goedert, “GSK3 inhibitors: development and therapeutic potential,” Nature Reviews Drug Discovery, vol. 3, no. 6, pp. 479–487, 2004.
View at: Google Scholar
L. Sereno, M. Coma, M. Rodriguez et al., “A novel GSK-3β inhibitor reduces Alzheimer's pathology and rescues neuronal loss in vivo,” Neurobiology of Disease, vol. 35, no. 3, pp. 359–367, 2009.
View at: Publisher Site | Google Scholar
A. Takashima, “Drug development targeting the glycogen synthase kinase-β(GSK- 3β)-mediated signal transduction pathway: role of GSK-β in adult brain,” Journal of Pharmacological Sciences, vol. 109, no. 2, pp. 174–178, 2009.
View at: Publisher Site | Google Scholar
K. Spittaels, C. van den Haute, J. van Dorpe et al., “Glycogen synthase kinase-β phosphorylates protein tau and rescues the axonopathy in the central nervous system of human four-repeat tau transgenic mice,” The Journal of Biological Chemistry, vol. 275, no. 52, pp. 41340–41349, 2000.
View at: Publisher Site | Google Scholar
R. V. Bhat, S. L. Budd Haeberlein, and J. Avila, “Glycogen synthase kinase-3: a drug target for CNS therapies,” Journal of Neurochemistry, vol. 89, no. 6, pp. 1313–1317, 2004.
View at: Publisher Site | Google Scholar
L. Feng, Y. Geisselbrecht, S. Blanck et al., “Structurally sophisticated octahedral metal complexes as highly selective protein kinase inhibitors,” Journal of the American Chemical Society, vol. 133, no. 15, pp. 5976–5986, 2011.
View at: Publisher Site | Google Scholar
H. Eldar-Finkelman, A. Licht-Murava, S. Pietrokovski, and M. Eisenstein, “Substrate competitive GSK-3 Inhibitors—strategy and Implications,” Biochimica et Biophysica Acta, vol. 1804, no. 3, pp. 598–603, 2010.
View at: Publisher Site | Google Scholar
A. Martinez, M. Alonso, A. Castro, C. Perez, and F. J. Moreno, “First non-ATP competitive glycogen synthase kinase-3β (GSK-β) inhibitors: thiadiazolidinones (TDZD) as potential drugs for the treatment of Alzheimer's disease,” Journal of Medicinal Chemistry, vol. 45, no. 6, pp. 1292–1299, 2002.
View at: Publisher Site | Google Scholar
A. Martinez, “Preclinical efficacy on GSK-3 inhibitors: towards a future generation of powerful drugs,” Medicinal Research Reviews, vol. 28, no. 5, pp. 773–796, 2008.
View at: Publisher Site | Google Scholar
A. Mora, G. Sabio, R. A. Gonzalez-Polo et al., “Lithium inhibits caspase 3 activation and dephosphorylation of PKB and GSK3 induced by K⁺ deprivation in cerebellar granule cells,” Journal of Neurochemistry, vol. 78, no. 1, pp. 199–206, 2001.
View at: Publisher Site | Google Scholar
W. J. Ryves and A. J. Harwood, “Lithium inhibits glycogen synthase kinase-3 by competition for magnesium,” Biochemical and Biophysical Research Communications, vol. 280, no. 3, pp. 720–725, 2001.
View at: Publisher Site | Google Scholar
B. Bax, P. S. Carter, C. Lewis et al., “The structure of phosphorylated GSK-β complexed with a peptide, FRATtide, that inhibits β-catenin phosphorylation,” Structure, vol. 9, no. 12, pp. 1143–1152, 2001.
View at: Publisher Site | Google Scholar
J. M. Domínguez, A. Fuertes, L. Orozco, M. del Monte-Millán, E. Delgado, and M. Medina, “Evidence for the irreversible inhibition of glycogen synthase kinas-3β by tideglusib,” The Journal of Biological Chemistry, vol. 287, pp. 893–904, 2012.
View at: Publisher Site | Google Scholar
D. G. Smith, M. Buffet, A. E. Fenwick et al., “3-Anilino-4-arylmaleimides: potent and selective inhibitors of glycogen synthase kinase-3 (GSK-3),” Bioorganic and Medicinal Chemistry Letters, vol. 11, no. 5, pp. 635–639, 2001.
View at: Publisher Site | Google Scholar
J. A. Bertrand, S. Thieffine, A. Vulpetti et al., “Structural characterization of the GSK-β active site using selective and non-selective ATP-mimetic inhibitors,” Journal of Molecular Biology, vol. 333, no. 2, pp. 393–407, 2003.
View at: Publisher Site | Google Scholar
M. P. Coghlan, A. A. Culbert, D. A. E. Cross et al., “Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription,” Chemistry and Biology, vol. 7, no. 10, pp. 793–803, 2000.
View at: Publisher Site | Google Scholar
D. A. E. Cross, A. A. Culbert, K. A. Chalmers, L. Facci, S. D. Skaper, and A. D. Reith, “Selective small-molecule inhibitors of glycogen synthase kinase-3 activity protect primary neurones from death,” Journal of Neurochemistry, vol. 77, no. 1, pp. 94–102, 2001.
View at: Publisher Site | Google Scholar
M. L. Selenica, H. S. Jensen, A. K. Larsen et al., “Efficacy of small-molecule glycogen synthase kinase-3 inhibitors in the postnatal rat model of tau hyperphosphorylation,” British Journal of Pharmacology, vol. 152, no. 6, pp. 959–979, 2007.
View at: Publisher Site | Google Scholar
D. J. O'Neill, L. Shen, C. Prouty et al., “Design, synthesis, and biological evaluation of novel 7-azaindolyl-heteroaryl-maleimides as potent and selective glycogen synthase kinase-β (GSK-β) inhibitors,” Bioorganic and Medicinal Chemistry, vol. 12, no. 12, pp. 3167–3185, 2004.
View at: Publisher Site | Google Scholar
H. C. Zhang, H. Ye, B. R. Conway et al., “3-(7-Azaindolyl)-4-arylmaleimides as potent, selective inhibitors of glycogen synthase kinase-3,” Bioorganic and Medicinal Chemistry Letters, vol. 14, no. 12, pp. 3245–3250, 2004.
View at: Publisher Site | Google Scholar
T. A. Engler, J. R. Henry, S. Malhotra et al., “Substituted 3-imidazo[1,2-a]pyridin-3-yl-4-(1,2,3,4-tetrahydro-[1,4] diazepino-[6,7,1-hi]indol-7-yl)pyrrole-2,5-diones as highly selective and potent inhibitors of glycogen synthase kinase-3,” Journal of Medicinal Chemistry, vol. 47, no. 16, pp. 3934–3937, 2004.
View at: Publisher Site | Google Scholar
T. A. Engler, S. Malhotra, T. P. Burkholder et al., “The development of potent and selective bisarylmaleimide GSK3 inhibitors,” Bioorganic and Medicinal Chemistry Letters, vol. 15, no. 4, pp. 899–903, 2005.
View at: Publisher Site | Google Scholar
Q. Ye, G. Xu, D. Lv, Z. Cheng, J. Li, and Y. Hu, “Synthesis and biological evaluation of novel 4-azaindolyl-indolyl-maleimides as glycogen synthase kinase-β (GSK-β) inhibitors,” Bioorganic and Medicinal Chemistry, vol. 17, no. 13, pp. 4302–4312, 2009.
View at: Publisher Site | Google Scholar
L. Gong, D. Hirschfeld, Y. C. Tan et al., “Discovery of potent and bioavailable GSK-β inhibitors,” Bioorganic and Medicinal Chemistry Letters, vol. 20, no. 5, pp. 1693–1696, 2010.
View at: Publisher Site | Google Scholar
D. I. Perez, V. Palomo, C. Perez et al., “Switching reversibility to irreversibility in glycogen synthase kinase-3 inhibitors: clues for specific design of new compounds,” Journal of Medicinal Chemistry, vol. 54, no. 12, pp. 4042–4056, 2011.
View at: Publisher Site | Google Scholar
I. Hers, J. M. Tavare, and R. M. Denton, “The protein kinase C inhibitors bisindolylmaleimide I (GF 109203x) and IX (Ro 31-8220) are potent inhibitors of glycogen synthase kinase-3 activity,” The FEBS Letters, vol. 460, no. 3, pp. 433–436, 1999.
View at: Publisher Site | Google Scholar
G. H. Kuo, C. Prouty, A. de Angelis et al., “Synthesis and discovery of macrocyclic polyoxygenated bis-7-azaindolylmaleimides as a novel series of potent and highly selective glycogen synthase kinase-β inhibitors,” Journal of Medicinal Chemistry, vol. 46, no. 19, pp. 4021–4031, 2003.
View at: Publisher Site | Google Scholar
H. C. Zhang, K. B. White, H. Ye et al., “Macrocyclic bisindolylmaleimides as inhibitors of protein kinase C and glycogen synthase kinase-3,” Bioorganic and Medicinal Chemistry Letters, vol. 13, no. 18, pp. 3049–3053, 2003.
View at: Publisher Site | Google Scholar
L. Shen, C. Prouty, B. R. Conway et al., “Synthesis and biological evaluation of novel macrocyclic bis-7-azaindolylmaleimides as potent and highly selective glycogen synthase kinase-β (GSK-β) inhibitors,” Bioorganic and Medicinal Chemistry, vol. 12, no. 5, pp. 1239–1255, 2004.
View at: Publisher Site | Google Scholar
H. C. Zhang, L. V. R. Bonaga, H. Ye, C. K. Derian, B. P. Damiano, and B. E. Maryanoff, “Novel bis(indolyl)maleimide pyridinophanes that are potent, selective inhibitors of glycogen synthase kinase-3,” Bioorganic and Medicinal Chemistry Letters, vol. 17, no. 10, pp. 2863–2868, 2007.
View at: Publisher Site | Google Scholar
A. P. Kozikowski, I. N. Gaisina, H. Yuan et al., “Structure-based design leads to the identification of lithium mimetics that block mania-like effects in rodents. Possible new GSK-β therapies for bipolar disorders,” Journal of the American Chemical Society, vol. 129, no. 26, pp. 8328–8332, 2007.
View at: Publisher Site | Google Scholar
I. N. Gaisina, F. Gallier, A. V. Ougolkov et al., “From a natural product lead to the identification of potent and selective benzofuran-3-yl-(indol-3-yl)maleimides as glycogen synthase kinase-β inhibitors that suppress proliferation and survival of pancreatic cancer cells,” Journal of Medicinal Chemistry, vol. 52, no. 7, pp. 1853–1863, 2009.
View at: Publisher Site | Google Scholar
H. Zhong, H. Zou, M. V. Semenov et al., “Characterization and development of novel small-molecules inhibiting GSK3 and activating Wnt signaling,” Molecular Biosystems, vol. 5, no. 11, pp. 1356–1360, 2009.
View at: Publisher Site | Google Scholar
H. Zou, L. Zhou, Y. Li et al., “Benzo[e]isoindole-1,3-diones as potential inhibitors of glycogen synthase kinase-3 (GSK-3). Synthesis, kinase inhibitory activity, zebrafish phenotype, and modeling of binding mode,” Journal of Medicinal Chemistry, vol. 53, no. 3, pp. 994–1003, 2010.
View at: Publisher Site | Google Scholar
A. Kozikowski and I. Gaysina, “3-Benzofuranyl-4-indolyl maleimides as potent GSK3 inhibitors for neurogenerative disorders,” WO 2008/077138 A1, 2008.
View at: Google Scholar
A. Kozikowski and I. Gaysina, “Benzofuran-3-yl(indol-3-yl) maleimides as potent GSK3 inhibitors,” US 2010/0004308 A1, 2010.
View at: Google Scholar
P. von Matt and J. Wagner, “Indolylmaleimide derivatives,” EP 2075249 A2, Novartis AG., 2009.
View at: Google Scholar
H. Zhang, B. Maryanoff, and H. Ye, “Substituted indazoly(indoly)maleimide derivatives as kinase inhibitors,” US 7439363 B2, Janssen Pharmaceutica N.V., 2008.
View at: Google Scholar
H. Zhang, B. Maryanoff, and H. Ye, “Substituted indazolyl (indolyl) maleimide derivatives as kinase inhibitors,” EP 1654255 B1, Janssen Pharmaceutica N.V., 2008.
View at: Google Scholar
S. Omura, Y. Iwai, A. Hirano et al., “A new alkaloid AM 2282 of Streptomyces origin taxonomy, fermentation, isolation and preliminary characterization,” Journal of Antibiotics, vol. 30, no. 4, pp. 275–282, 1977.
View at: Google Scholar
N. Funato, H. Takayanagi, Y. Konda et al., “Absolute configuration of staurosporine by X-ray analysis,” Tetrahedron Letters, vol. 35, no. 8, pp. 1251–1254, 1994.
View at: Publisher Site | Google Scholar
S. Leclerc, M. Garnier, R. Hoessel et al., “Indirubins inhibit glycogen synthase kinase-β and CDK5/P25, two protein kinases involved in abnormal tau phosphorylation in Alzheimer's disease. A property common to most cyclin-dependent kinase inhibitors?” The Journal of Biological Chemistry, vol. 276, no. 1, pp. 251–260, 2001.
View at: Publisher Site | Google Scholar
H. Bregman, D. S. Williams, G. E. Atilla, P. J. Carroll, and E. Meggers, “An organometallic inhibitor for glycogen synthase kinase-3,” Journal of the American Chemical Society, vol. 126, no. 42, pp. 13594–13595, 2004.
View at: Publisher Site | Google Scholar
G. E. Atilla-Gokcumen, D. S. Williams, H. Bregman, N. Pagano, and E. Meggers, “Organometallic compounds with biological activity: a very selective and highly potent cellular inhibitor for glycogen synthase kinase-3,” ChemBioChem, vol. 7, no. 9, pp. 1443–1450, 2006.
View at: Publisher Site | Google Scholar
G. E. Atilla-Gokcumen, N. Pagano, C. Streu et al., “Extremely tight binding of a ruthenium complex to glycogen synthase kinase-3,” ChemBioChem, vol. 9, no. 18, pp. 2933–2936, 2008.
View at: Google Scholar
G. E. Atilla-Gokcumen, L. di Costanzo, and E. Meggers, “Structure of anticancer ruthenium half-sandwich complex bound to glycogen synthase kinase-3β,” Journal of Biological Inorganic Chemistry, vol. 16, no. 1, pp. 45–50, 2011.
View at: Publisher Site | Google Scholar
L. Meijer, A. L. Skaltsounis, P. Magiatis et al., “GSK-3-selective inhibitors derived from Tyrian purple indirubins,” Chemistry and Biology, vol. 10, no. 12, pp. 1255–1266, 2003.
View at: Publisher Site | Google Scholar
P. Polychronopoulos, P. Magiatis, A. L. Skaltsounis et al., “Structural basis for the synthesis of indirubins as potent and selective inhibitors of glycogen synthase kinase-3 and cyclin-dependent kinases,” Journal of Medicinal Chemistry, vol. 47, no. 4, pp. 935–946, 2004.
View at: Publisher Site | Google Scholar
K. Vougogiannopoulou, Y. Ferandin, K. Bettayeb et al., “Soluble 3′,6-substituted indirubins with enhanced selectivity toward glycogen synthase kinase-3 alter circadian period,” Journal of Medicinal Chemistry, vol. 51, no. 20, pp. 6421–6431, 2008.
View at: Publisher Site | Google Scholar
A. Beauchard, H. Laborie, H. Rouillard et al., “Synthesis and kinase inhibitory activity of novel substituted indigoids,” Bioorganic and Medicinal Chemistry, vol. 17, no. 17, pp. 6257–6263, 2009.
View at: Publisher Site | Google Scholar
D. Beher, M. Bettai, I. Churcher et al., “1-alkyl-3-thio-substituted indole-2-alkynoic acids useful for the treatment for Alzheimer's disease and related conditions,” EP 1708997 B1, Merck and Company, Inc., 2009.
View at: Google Scholar
S. Berg, S. Hellberg, M. Nylöf, and Y. Xue, “3-Heterocyclyl-indole inhibitors of glycogen synthase kinase-3,” US 7399780 B2, Astra Zeneca AB., 2008.
View at: Google Scholar
S. Berg, S. Hellberg, M. Nylöf, and Y. Xue, “2-hydroxy-3-heteroarylindole derivatives as GSK3 inhibitors,” EP 1492785 B1, Astra Zeneca AB., 2008.
View at: Google Scholar
J. Green, A. Miller, J. Jimenez et al., “Azaindoles useful as inhibitors of rock and other protein kinases,” US 7514448 B2, Vertex Pharmaceuticals Inc., 2009.
View at: Google Scholar
A. Heckel, G. Roth, J. Kley, S. Hoerer, and I. Uphues, “Novel alkyl-containing 5-acylindolinones, their preparation and their use as pharmaceutical products,” WO 2005/087727 A1, Boehringer Ingelheim Pharma GmbH & Company KG., 2005.
View at: Google Scholar
A. Heckel, G. Roth, J. Kley, S. Hoerer, and I. Uphues, “Cycloalkyl—containing 5-acylindolinones, the preparation thereof and their use as medicaments,” WO 7262206 B2, Boehringer Ingelheim International GmbH., 2007.
View at: Google Scholar
A. Heckel, G. Roth, J. Kley, S. Hoerer, and I. Uphues, “Aryl-containing 5-acylindolinones, the preparation thereof and their use as medicaments,” US 7176231 B2, Boehringer Ingelheim International GmbH., 2007.
View at: Google Scholar
A. Heckel, G. Roth, J. Kley, S. Hoerer, and I. Uphues, “Alkyl-containing 5-acylindolinones, the preparation thereof and their use as medicaments,” US 7560480 B2, Boehringer Ingelheim Pharma GmbH & Company KG., 2009.
View at: Google Scholar
L. Meijer, P. Greengard, M. Knockaert, and A. Skaltsounis, “Indirubin-type compounds, compositions, and methods for their use,” US 2007/0276025 A1, 2007.
View at: Google Scholar
M. Leost, C. Schultz, A. Link et al., “Paullones are potent inhibitors of glycogen synthase kinase-β and cyclin-dependent kinase 5/p25,” European Journal of Biochemistry, vol. 267, no. 19, pp. 5983–5994, 2000.
View at: Publisher Site | Google Scholar
C. Schultz, A. Link, M. Leost et al., “Paullones, a series of cyclin-dependent kinase inhibitors: synthesis, evaluation of CDK1/cyclin B inhibition, and in vitro antitumor activity,” Journal of Medicinal Chemistry, vol. 42, no. 15, pp. 2909–2919, 1999.
View at: Publisher Site | Google Scholar
M. Knockaert, K. Wieking, S. Schmitt et al., “Intracellular targets of paullones: identification following affinity purification on immobilized inhibitor,” The Journal of Biological Chemistry, vol. 277, no. 28, pp. 25493–25501, 2002.
View at: Publisher Site | Google Scholar
C. Kunick, K. Lauenroth, M. Leost, L. Meijer, and T. Lemcke, “1-Azakenpaullone is a selective inhibitor of glycogen synthase kinase-β,” Bioorganic and Medicinal Chemistry Letters, vol. 14, no. 2, pp. 413–416, 2004.
View at: Publisher Site | Google Scholar
C. Kunick, Z. Zeng, R. Gussio et al., “Structure-aided of optimization of kinase inhibitors derived from alsterpaullone,” ChemBioChem, vol. 6, no. 3, pp. 541–549, 2005.
View at: Publisher Site | Google Scholar
L. Meijer and C. Kunick, “Use of paullone derivatives for making medicines,” WO 2001/060374 A1, 2001.
View at: Google Scholar
J. Witherington, V. Bordas, S. L. Garland et al., “5-Aryl-pyrazolo[3,4-b]pyridines: potent inhibitors of glycogen synthase kinase-3 (GSK-3),” Bioorganic and Medicinal Chemistry Letters, vol. 13, no. 9, pp. 1577–1580, 2003.
View at: Publisher Site | Google Scholar
J. Witherington, V. Bordas, D. Haigh et al., “5-Aryl-pyrazolo[3,4-b]pyridazines: potent inhibitors of glycogen synthase kinase-3 (GSK-3),” Bioorganic and Medicinal Chemistry Letters, vol. 13, no. 9, pp. 1581–1584, 2003.
View at: Publisher Site | Google Scholar
J. Witherington, V. Bordas, A. Gaiba et al., “6-Aryl-pyrazolo[3,4-b]pyridines: potent inhibitors of glycogen synthase kinase-3 (GSK-3),” Bioorganic and Medicinal Chemistry Letters, vol. 13, no. 18, pp. 3055–3057, 2003.
View at: Publisher Site | Google Scholar
J. Witherington, V. Bordas, A. Gaiba et al., “6-Heteroaryl-pyrazolo[3,4-b]pyridines: potent and selective inhibitors of glycogen synthase kinase-3 (GSK-3),” Bioorganic and Medicinal Chemistry Letters, vol. 13, no. 18, pp. 3059–3062, 2003.
View at: Publisher Site | Google Scholar
Y. Uno, H. Iwashita, T. Tsukamoto et al., “Efficacy of a novel, orally active GSK-3 inhibitor 6-Methyl-N-[3-[[3-(1-methylethoxy)propyl]carbamoyl]-1H-pyrazol-4-yl]pyridine-3-carboxamide in tau transgenic mice,” Brain Research, vol. 1296, pp. 148–163, 2009.
View at: Publisher Site | Google Scholar
K. L. Kees, T. J. Caggiano, K. E. Steiner et al., “Studies on new acidic azoles as glucose-lowering agents in obese, diabetic db/db mice,” Journal of Medicinal Chemistry, vol. 38, no. 4, pp. 617–628, 1995.
View at: Google Scholar
K. L. Kees, J. J. Fitzgerald Jr., K. E. Steiner et al., “New potent antihyperglycemic agents in db/db mice: synthesis and structure-activity relationship studies of (4-substituted benzyl)(trifluoromethyl)pyrazoles and -pyrazolones,” Journal of Medicinal Chemistry, vol. 39, no. 20, pp. 3920–3928, 1996.
View at: Publisher Site | Google Scholar
G. R. Bebernitz, G. Argentieri, B. Battle et al., “The effect of 1,3-diaryl-[1H]-pyrazole-4-acetamides on glucose utilization in ob/ob mice,” Journal of Medicinal Chemistry, vol. 44, no. 16, pp. 2601–2611, 2001.
View at: Publisher Site | Google Scholar
D. M. Shen, E. J. Brady, M. R. Candelore et al., “Discovery of novel, potent, selective, and orally active human glucagon receptor antagonists containing a pyrazole core,” Bioorganic and Medicinal Chemistry Letters, vol. 21, no. 1, pp. 76–81, 2011.
View at: Publisher Site | Google Scholar
A. J. Peat, D. Garrido, J. A. Boucheron et al., “Novel GSK-3 inhibitors with improved cellular activity,” Bioorganic and Medicinal Chemistry Letters, vol. 14, no. 9, pp. 2127–2130, 2004.
View at: Publisher Site | Google Scholar
C. Lum, J. Kahl, L. Kessler et al., “2,5-Diaminopyrimidines and 3,5-disubstituted azapurines as inhibitors of glycogen synthase kinase-3 (GSK-3),” Bioorganic and Medicinal Chemistry Letters, vol. 18, no. 12, pp. 3578–3581, 2008.
View at: Publisher Site | Google Scholar
A. M. Aronov, T. Qing, G. Martinez-Botella et al., “Structure-guided design of potent and selective pyrimidylpyrrole inhibitors of extracellular signal-regulated kinase (ERK) using conformational control,” Journal of Medicinal Chemistry, vol. 52, no. 20, pp. 6362–6368, 2009.
View at: Publisher Site | Google Scholar
D. B. Ring, K. W. Johnson, E. J. Henriksen et al., “Selective glycogen synthase kinase-3 inhibitors potentiate insulin activation of glucose transport and utilization in vitro and in vivo,” Diabetes, vol. 52, no. 3, pp. 588–595, 2003.
View at: Publisher Site | Google Scholar
Y. Maeda, M. Nakano, H. Sato et al., “4-Acylamino-6-arylfuro[2,3-d]pyrimidines: potent and selective glycogen synthase kinase-3 inhibitors,” Bioorganic and Medicinal Chemistry Letters, vol. 14, no. 15, pp. 3907–3911, 2004.
View at: Publisher Site | Google Scholar
Y. Miyazaki, Y. Maeda, H. Sato, M. Nakano, and G. W. Mellor, “Rational design of 4-amino-5,6-diaryl-furo[2,3-d]pyrimidines as potent glycogen synthase kinase-3 inhibitors,” Bioorganic and Medicinal Chemistry Letters, vol. 18, no. 6, pp. 1967–1971, 2008.
View at: Publisher Site | Google Scholar
D. Bebbington, Binch H., R. Knegtel et al., “Pyrazole compounds useful as protein kinase inhibitors,” US 6660731 B2, Vertex Pharmaceuticals Inc., 2003.
View at: Google Scholar
D. Bebbington, H. Binch, R. Knegtel et al., “Fused pyrimidyl pyrazole compounds useful as protein kinase inhibitors,” US 7008948 B2, Vertex Pharmaceuticals Inc., 2006.
View at: Google Scholar
D. Bebbington and J. Charrier, “Pyrazole compounds useful as protein kinase inhibitors,” US 6656939 B2, Vertex Pharmaceuticals Inc., 2003.
View at: Google Scholar
D. Bebbington, J. Charrier, R. Davies et al., “Pyrazole compounds useful as protein kinase inhibitors,” US 6989385 B2, Vertex Pharmaceuticals Inc., 2006.
View at: Google Scholar
D. Bebbington, J. Charrier, R. Davies et al., “Pyrazole compounds useful as protein kinase inhibitors,” WO 2002/059111 A2, Vertex Pharmaceuticals Inc., 2002.
View at: Google Scholar
D. Bebbington, J. Charrier, R. Davies et al., “Pyrazole compounds useful as protein kinase inhibitors,” US 6653301 B2, Vertex Pharmaceuticals Inc., 2003.
View at: Google Scholar
D. Bebbington, J. Charrier, J. Golec, A. Miller, and R. Knegtel, “Pyrazole compounds useful as protein kinase inhibitors,” WO 2002/057259 A2, Vertex Pharmaceuticals Inc., 2002.
View at: Google Scholar
D. Bebbington, J. Charrier, J. Golec, A. Miller, and R. Knegtel, “Pyrazole compounds useful as protein kinase inhibitors,” US 6664247 B2, Vertex Pharmaceuticals Inc., 2003.
View at: Google Scholar
D. Bebbington, J. Charrier, J. Golec, and F. Pierard, “Pyrazole compounds useful as protein kinase inhibitors,” US 6727251 B2, Vertex Pharmaceuticals Inc., 2004.
View at: Google Scholar
D. Bebbington, J. Charrier, J. Golec, and F. Pierard, “Pyrazole compounds useful as protein kinase inhibitors,” US 7427681 B2, Vertex Pharmaceuticals Inc., 2008.
View at: Google Scholar
R. Davies, D. Bebbington, R. Knegtel et al., “Fusion joining device for plastic tubes,” US 39081 B2, Vertex Pharmaceuticals Inc., 2008.
View at: Google Scholar
R. Davies, P. Li, J. Golec, J. Charrier, R. Knegtel, and D. Bebbington, “Pyrazole compounds useful as protein kinase inhibitors,” US 6610677 B2, Vertex Pharmaceuticals Inc., 2003.
View at: Google Scholar
E. Freyne, C. Love, L. Cooymans et al., “Triazolopyrimidine derivatives as glycogen synthase kinase 3 inhibitors,” US 7449465 B2, Janssen Pharmaceutica, 2008.
View at: Google Scholar
E. Freyne, C. Love, L. Cooymans et al., “Triazolopyrimidine derivatives as glycogen synthase kinase-3 inhibitors,” US 7560458 B2, Janssen Pharmaceutica, 2009.
View at: Google Scholar
A. Garcia, T. Gallet, A. Taki Li et al., “2-pyridinyl-6,7,8,9-tetrahydropyrimido[1,2-a] pyrimidin-4-one and 7-pyridinyl-2,3-dihydroimidazo[1,2-a] pyrimidin-5(1H)one derivatives,” US 7566720 B2, Sanofi-Aventis Mitsubishi Pharma Corporation, 2009.
View at: Google Scholar
P. George, A. Lochead, M. Saady, F. Slowinski, and P. Yaiche, “Substituted 8′-pyridinyl-dihydrospiro-[cycloalkyl]-pyrimido[1,2-a] pyrimidin-6-one and 8′-pyrimidinyl-dihydrospiro-[cycloalkyl]-pyrimido[1,2-a] pyrimidin-6-one derivatives,” US 7507743 B2, Sanofi-Aventis Mitsubishi Pharma Corporation, 2009.
View at: Google Scholar
D. Goff, S. Harrison, J. Nuss, D. Ring, and X. Zhou, “Inhibitors of glycogen synthase kinase 3,” US 6417185 B1, Chiron Corporation, 2002.
View at: Google Scholar
K. Kataoka, T. Kosugi, T. Ishii et al., “Substituted pyrrolo[3,2-d]pyrimidines as glycogen synthase kinase (GSK) inhibitors,” US 7528140 B2, Teijin Limited, 2009.
View at: Google Scholar
K. Kataoka, T. Kosugi, T. Ishii et al., “Pyrrolopyrimidine derivative,” EP 1477490 A1, Teijin Limited, 2004.
View at: Google Scholar
R. Knegtel, D. Bebbington, H. Binch et al., “Pyrazole compounds useful as protein kinase inhibitors,” US 6613776 B2, Vertex Pharmaceuticals Inc., 2003.
View at: Google Scholar
A. Lochead, S. Marguerie, M. Saady, and P. Yaiche, “1-[alkyl], 1-[(heteroaryl)alkyl] and 1-[(aryl)alkyl]-7-pyridinyl-imidazo[1,2-a]pyrimidin-5(1h)-one derivatives,” US 7608624 B2, Sanofi-Aventis Mitsubishi Pharma Corporation, 2009.
View at: Google Scholar
M. Nakano and Y. Maeda, “Novel chemical compounds,” WO 2005/061516 A1, Smithkline Beecham Corporation, 2005.
View at: Google Scholar
J. Nuss, S. Harrison, D. Ring et al., “Inhibitors of glycogen synthase kinase-3,” US 6489344 B1, Chiron Corporation, 2002.
View at: Google Scholar
J. Nuss, S. Harrison, D. Ring et al., “Inhibitors of glycogen synthase kinase-3,” US 7037918 B2, Chiron Corporation, 2006.
View at: Google Scholar
J. Nuss, S. Harrison, D. Ring et al., “Inhibitors of glycogen synthase kinase-3,” US 7045519 B2, Chiron Corporation, 2006.
View at: Google Scholar
T. Tsutsumi, S. Sugiura, M. Koga et al., “Substituted pyrrolo[3,2-d]pyrimidine derivatives,” US 7557113 B2, Teijin Pharma Limited, 2009.
View at: Google Scholar
P. H. Olesen, A. R. Sorensen, B. Urso et al., “Synthesis and in vitro characterization of 1-(4-aminofurazan-3-yl)-5-dialkylaminomethyl-1H-[1,2,3]triazole-4-carboxylic acid derivatives. A new class of selective GSK-3 inhibitors,” Journal of Medicinal Chemistry, vol. 46, no. 15, pp. 3333–3341, 2003.
View at: Publisher Site | Google Scholar
U. Bandarage, B. Hare, J. Parsons et al., “4-(Benzimidazol-2-yl)-1,2,5-oxadiazol-3-ylamine derivatives: potent and selective p70S6 kinase inhibitors,” Bioorganic and Medicinal Chemistry Letters, vol. 19, no. 17, pp. 5191–5194, 2009.
View at: Publisher Site | Google Scholar
M. Saitoh, J. Kunitomo, E. Kimura et al., “Design, synthesis and structure-activity relationships of 1,3,4-oxadiazole derivatives as novel inhibitors of glycogen synthase kinase-β,” Bioorganic and Medicinal Chemistry, vol. 17, no. 5, pp. 2017–2029, 2009.
View at: Publisher Site | Google Scholar
M. Saitoh, J. Kunitomo, E. Kimura et al., “2-{3-[4-(Alkylsulfinyl)phenyl]-1-benzofuran-5-yl}-5-methyl-1,3,4-oxadiazole derivatives as novel inhibitors of glycogen synthase kinase-β with good brain permeability,” Journal of Medicinal Chemistry, vol. 52, no. 20, pp. 6270–6286, 2009.
View at: Publisher Site | Google Scholar
T. Onishi, H. Iwashita, Y. Uno et al., “A novel glycogen synthase kinase-3 inhibitor 2-methyl-5-(3-{4-[(S)- methylsulfinyl]phenyl}-1-benzofuran-5-yl)-1,3,4-oxadiazole decreases tau phosphorylation and ameliorates cognitive deficits in a transgenic model of Alzheimer's disease,” Journal of Neurochemistry, vol. 119, no. 6, pp. 1330–1340, 2011.
View at: Publisher Site | Google Scholar
M. A. Khanfar, R. A. Hill, A. Kaddoumi, and K. A. El Sayed, “Discovery of novel GSK-β inhibitors with potent in vitro and in vivo activities and excellent brain permeability using combined ligand- and structure-based virtual screening,” Journal of Medicinal Chemistry, vol. 53, no. 24, pp. 8534–8545, 2010.
View at: Publisher Site | Google Scholar
A. G. Koryakova, Y. A. Ivanenkov, E. A. Ryzhova et al., “Novel aryl and heteroaryl substituted N-[3-(4-phenylpiperazin-1-yl)propyl]-1,2,4-oxadiazole-5-carboxamides as selective GSK-3 inhibitors,” Bioorganic and Medicinal Chemistry Letters, vol. 18, no. 12, pp. 3661–3666, 2008.
View at: Publisher Site | Google Scholar
C. Loge, A. Testard, V. Thiery et al., “Novel 9-oxo-thiazolo[5,4-f]quinazoline-2-carbonitrile derivatives as dual cyclin-dependent kinase 1 (CDK1)/glycogen synthase kinase-3 (GSK-3) inhibitors: synthesis, biological evaluation and molecular modeling studies,” European Journal of Medicinal Chemistry, vol. 43, no. 7, pp. 1469–1477, 2008.
View at: Publisher Site | Google Scholar
R. Bhat, Y. Xue, S. Berg et al., “tructural insights and biological effects of glycogen synthase kinase-3-specific inhibitor AR-A014418,” The Journal of Biological Chemistry, vol. 278, no. 46, pp. 45937–45945, 2003.
View at: Publisher Site | Google Scholar
W. Noble, E. Planel, C. Zehr et al., “Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 19, pp. 6990–6995, 2005.
View at: Publisher Site | Google Scholar
F. Lo Monte, T. Kramer, A. Bolander et al., “Synthesis and biological evaluation of glycogen synthase kinase-3 (GSK-3) inhibitors: an fast and atom efficient access to 1-aryl-3-benzylureas,” Bioorganic and Medicinal Chemistry Letters, vol. 21, no. 18, pp. 5610–5615, 2011.
View at: Publisher Site | Google Scholar
D. Shin, S. C. Lee, Y. S. Heo et al., “Design and synthesis of 7-hydroxy-1H-benzoimidazole derivatives as novel inhibitors of glycogen synthase kinase-β,” Bioorganic and Medicinal Chemistry Letters, vol. 17, no. 20, pp. 5686–5689, 2007.
View at: Publisher Site | Google Scholar
B. Voigt, M. Krug, C. Schachtele, F. Totzke, and A. Hilgeroth, “Probing novel 1-aza-9-oxafluorenes as selective GSK-β inhibitors,” ChemMedChem, vol. 3, no. 1, pp. 120–126, 2008.
View at: Publisher Site | Google Scholar
N. B. Chauhan, G. J. Siegel, and D. L. Feinstein, “Propentofylline attenuates tau hyperphosphorylation in Alzheimer's Swedish mutant model Tg2576,” Neuropharmacology, vol. 48, no. 1, pp. 93–104, 2005.
View at: Publisher Site | Google Scholar
M. Arnost, A. Pierce, E. ter Haar et al., “3-Aryl-4-(arylhydrazono)-1H-pyrazol-5-ones: highly ligand efficient and potent inhibitors of GSKβ,” Bioorganic and Medicinal Chemistry Letters, vol. 20, no. 5, pp. 1661–1664, 2010.
View at: Publisher Site | Google Scholar
W. Chen, I. N. Gaisina, H. Gunosewoyo et al., “Structure-guided design of a highly selective glycogen synthase kinase-3β inhibitor: a superior neuroprotective pyrazolone showing antimania effects,” ChemMedChem, vol. 6, pp. 1587–1592, 2011.
View at: Google Scholar
M. A. Khanfar, B. A. Asal, M. Mudit, A. Kaddoumi, and K. A. El Sayed, “The marine natural-derived inhibitors of glycogen synthase kinase-β phenylmethylene hydantoins: in vitro and in vivo activities and pharmacophore modeling,” Bioorganic and Medicinal Chemistry, vol. 17, no. 16, pp. 6032–6039, 2009.
View at: Publisher Site | Google Scholar
K. Coffman, M. Brodney, J. Cook et al., “6-amino-4-(pyrimidin-4-yl)pyridones: novel glycogen synthase kinase-3β inhibitors,” Bioorganic and Medicinal Chemistry Letters, vol. 21, pp. 1429–1433, 2011.
View at: Google Scholar
M. Hamann, D. Alonso, E. Martin-Aparicio et al., “Glycogen synthase kinase-3 (GSK-3) inhibitory activity and structure-activity relationship (SAR) studies of the manzamine alkaloids. Potential for Alzheimer's disease,” Journal of Natural Products, vol. 70, no. 9, pp. 1397–1405, 2007.
View at: Publisher Site | Google Scholar
M. Gompel, M. Leost, E. B. de Kier Joffe et al., “Meridianins, a new family of protein kinase inhibitors isolated from the ascidian Aplidium meridianum,” Bioorganic and Medicinal Chemistry Letters, vol. 14, no. 7, pp. 1703–1707, 2004.
View at: Publisher Site | Google Scholar
L. Meijer, A. M. W. H. Thunnissen, A. W. White et al., “Inhibition of cyclin-dependent kinases, GSK-β and CK1 by hymenialdisine, a marine sponge constituent,” Chemistry and Biology, vol. 7, no. 1, pp. 51–63, 2000.
View at: Publisher Site | Google Scholar
N. Zhang, R. Zhong, H. Yan, and Y. Jiang, “Structural features underlying selective inhibition of GSK3β by dibromocantharelline: implications for rational drug design,” Chemical Biology and Drug Design, vol. 77, no. 3, pp. 199–205, 2011.
View at: Publisher Site | Google Scholar
V. Pande and M. J. Ramos, “Structural basis for the GSK-β binding affinity and selectivity against CDK-2 of 1-(4-aminofurazan-3yl)-5-dialkylaminomethyl-1H-[1,2,3] triazole-4-carboxylic acid derivatives,” Bioorganic and Medicinal Chemistry Letters, vol. 15, no. 23, pp. 5129–5135, 2005.
View at: Publisher Site | Google Scholar
E. ter Haar, J. T. Coll, D. A. Austen, H. M. Hsiao, L. Swenson, and J. Jain, “Structure of GSKβ reveals a primed phosphorylation mechanism,” Nature Structural Biology, vol. 8, no. 7, pp. 593–596, 2001.
View at: Publisher Site | Google Scholar
J. Gotz and L. M. Ittner, “Animal models of Alzheimer's disease and frontotemporal dementia,” Nature Reviews Neuroscience, vol. 9, no. 7, pp. 532–544, 2008.
View at: Publisher Site | Google Scholar
K. Iijima-Ando and K. Iijima, “Transgenic drosophila models of Alzheimer's disease and tauopathies,” Brain Structure and Function, vol. 214, no. 2-3, pp. 245–262, 2010.
View at: Publisher Site | Google Scholar
J. Wentzell and D. Kretzschmar, “Alzheimer's disease and tauopathy studies in flies and worms,” Neurobiology of Disease, vol. 40, no. 1, pp. 21–28, 2010.
View at: Publisher Site | Google Scholar
J. J. Lucas, F. Hernandez, P. Gomez-Ramos, M. A. Moran, R. Hen, and J. Avila, “Decreased nuclear β-catenin, tau hyperphosphorylation and neurodegeneration in GSK-3β conditional transgenic mice,” The EMBO Journal, vol. 20, no. 1-2, pp. 27–39, 2001.
View at: Google Scholar
M. Perez, E. Ribe, A. Rubio et al., “Characterization of a double (amyloid precursor protein-tau) transgenic: tau phosphorylation and aggregation,” Neuroscience, vol. 130, no. 2, pp. 339–347, 2005.
View at: Publisher Site | Google Scholar
E. M. Ribe, M. Perez, B. Puig et al., “Accelerated amyloid deposition, neurofibrillary degeneration and neuronal loss in double mutant APP/tau transgenic mice,” Neurobiology of Disease, vol. 20, no. 3, pp. 814–822, 2005.
View at: Publisher Site | Google Scholar
D. Terwel, D. Muyllaert, I. Dewachter et al., “Amyloid activates GSK-β to aggravate neuronal tauopathy in bigenic mice,” American Journal of Pathology, vol. 172, no. 3, pp. 786–798, 2008.
View at: Publisher Site | Google Scholar
J. Lewis, D. W. Dickson, W. L. Lin et al., “Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP,” Science, vol. 293, no. 5534, pp. 1487–1491, 2001.
View at: Publisher Site | Google Scholar
S. Oddo, A. Caccamo, J. D. Shepherd et al., “Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Aβ and synaptic dysfunction,” Neuron, vol. 39, no. 3, pp. 409–421, 2003.
View at: Publisher Site | Google Scholar
J. Lewis, E. McGowan, J. Rockwood et al., “Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L)tau protein,” Nature Genetics, vol. 25, no. 4, pp. 402–405, 2000.
View at: Publisher Site | Google Scholar
D. Paquet, R. Bhat, A. Sydow et al., “A zebrafish model of tauopathy allows in vivo imaging of neuronal cell death and drug evaluation,” Journal of Clinical Investigation, vol. 119, no. 5, pp. 1382–1395, 2009.
View at: Publisher Site | Google Scholar
D. Paquet, B. Schmid, and C. Haass, “Transgenic zebrafish as a novel animal model to study tauopathies and other neurodegenerative disorders in vivo,” Neurodegenerative Diseases, vol. 7, no. 1–3, pp. 99–102, 2010.
View at: Publisher Site | Google Scholar
Y. Okawa, K. Ishiguro, and S. C. Fujita, “Stress-induced hyperphosphorylation of tau in the mouse brain,” The FEBS Letters, vol. 535, no. 1–3, pp. 183–189, 2003.
View at: Publisher Site | Google Scholar
S. Yoshida, M. Maeda, S. Kaku, H. Ikeya, K. Yamada, and S. Nakaike, “Lithium inhibits stress-induced changes in tau phosphorylation in the mouse hippocampus,” Journal of Neural Transmission, vol. 113, no. 11, pp. 1803–1814, 2006.
View at: Publisher Site | Google Scholar
K. Leroy and J. P. Brion, “Developmental expression and localization of glycogen synthase kinase-β in rat brain,” Journal of Chemical Neuroanatomy, vol. 16, no. 4, pp. 279–293, 1999.
View at: Publisher Site | Google Scholar
M. Takahashi, K. Tomizawa, and K. Ishiguro, “Distribution of tau protein kinase I/glycogen synthase kinase-β, phosphatases 2A and 2B, and phosphorylated tau in the developing rat brain,” Brain Research, vol. 857, no. 1-2, pp. 193–206, 2000.
View at: Publisher Site | Google Scholar
S. H. Min, J. S. Cho, J. H. Oh et al., “Tau and GSKβ dephosphorylations are required for regulating Pin1 phosphorylation,” Neurochemical Research, vol. 30, no. 8, pp. 955–961, 2005.
View at: Publisher Site | Google Scholar
N. Sato, L. Meijer, L. Skaltsounis, P. Greengard, and A. H. Brivanlou, “Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor,” Nature Medicine, vol. 10, no. 1, pp. 55–63, 2004.
View at: Publisher Site | Google Scholar
T. D. Gould, N. A. Gray, and H. K. Manji, “Effects of a glycogen synthase kinase-3 inhibitor, lithium, in adenomatous polyposis coli mutant mice,” Pharmacological Research, vol. 48, no. 1, pp. 49–53, 2003.
View at: Publisher Site | Google Scholar
A. Martinez, A. Castro, and M. Medina, Glycogen Synthase Kinase-3 (GSK-3) and Its Inhibitors, John Wiley & Sons, Hoboken, NJ, USA, 2006.
A. Martinez, C. Gil, and D. I. Perez, “Glycogen synthase kinase-3 inhibitors in the next horizon for Alzheimer's disease treatment,” International Journal of Alzheimer's Disease, vol. 2011, Article ID 280502, 7 pages, 2011.
View at: Publisher Site | Google Scholar
L. T. Alon, S. Pietrokovski, S. Barkan et al., “Selective loss of glycogen synthase kinase-3α in birds reveals distinct roles for GSK-3 isozymes in tau phosphorylation,” The FEBS Letters, vol. 585, no. 8, pp. 1158–1162, 2011.
View at: Publisher Site | Google Scholar
C. J. Phiel, C. A. Wilson, V. M. Y. Lee, and P. S. Klein, “GSK-3α regulates production of Alzheimer's disease amyloid-β peptides,” Nature, vol. 423, no. 6938, pp. 435–439, 2003.
View at: Publisher Site | Google Scholar
M. I. Davis, J. P. Hunt, S. Herrgard et al., “Comprehensive analysis of kinase inhibitor selectivity,” Nature Biotechnology, vol. 29, no. 11, pp. 1046–1051, 2011.
View at: Publisher Site | Google Scholar
D. Rauh, “Inaktive Kinasekonformationen stabilisieren,” Nachrichten aus der Chemie, vol. 58, no. 2, pp. 118–121, 2010.
View at: Publisher Site | Google Scholar
K. Okada, T. Sato, Y. Kohno, and M. Nomura, “7-Cycloalkylaminoquinolones as GSK-3 inhibitors,” WO 2010/104205 A1, Kyorin Pharmaceutical Company Limited, 2010.
View at: Google Scholar
S. C. Turner, M. H. M. Bakker, W. Hornberger, and F. E. Wolter, “Heterocyclic compounds and their use as glycogen synthase kinase-3 inhibitors,” WO 2010/109005 A1, Abbott GmbH & Co. KG., 2010.
View at: Google Scholar

Copyright

Copyright © 2012 Thomas Kramer et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation

Download other formats

Order printed copies

Views

19232

Downloads

5970

Citations