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Tideglusib

Tideglusib is a small-molecule, thiadiazolidinone-based compound that functions as a selective, irreversible, non-ATP competitive inhibitor of glycogen synthase kinase-3 beta (GSK-3β), a serine/threonine kinase implicated in numerous cellular processes including tau hyperphosphorylation, amyloid-beta accumulation, and Wnt signaling dysregulation.^[1] Originally developed by the Spanish pharmaceutical company Noscira (part of the Zeltia group) under the code NP-12, it targets neurodegenerative and neuromuscular disorders by modulating GSK-3β activity to promote neuroprotection, synaptic plasticity, and reduced inflammation without broadly affecting ATP-dependent kinase functions.^[2] First investigated in the mid-2000s for Alzheimer's disease (AD), Tideglusib advanced to phase 2 clinical trials, where it demonstrated trends toward improved cognition in mild-to-moderate AD patients over 24 weeks, alongside a favorable safety profile with mild gastrointestinal side effects like diarrhea reported in 13-18% of participants.^[3] However, following unsuccessful phase 2b outcomes in 2011-2012, development for AD was discontinued due to insufficient efficacy against primary endpoints, though it showed promise in reducing tau pathology and amyloid plaque load in preclinical models.^[1] Subsequent research has repurposed Tideglusib for other GSK-3β-related conditions, including progressive supranuclear palsy, autism spectrum disorders, and congenital myotonic dystrophy type 1 (DM1), where phase 2/3 trials (e.g., NCT03692312, which showed mixed results with positive secondary outcomes in 2023) evaluated its safety and potential to improve muscle function and RNA splicing defects via GSK-3β inhibition of CUGBP1 protein.^[4]^[5] As of 2025, Tideglusib remains investigational with no regulatory approvals, but ongoing and expanded access programs highlight its versatility; for instance, a phase 2 trial (NCT05004129) assesses weight-adjusted dosing in DM1 over 52 weeks. Currently developed by AMO Pharma as AMO-02, recent long-term safety data from the REACHCDM-X study support its continued evaluation in DM1, with FDA discussions planned for late 2025.^[6] Preclinical data support exploration in alcohol use disorder (AUD) by reducing binge ethanol intake through modulation of synaptic genes, and in arrhythmogenic cardiomyopathy via Wnt pathway correction.^[2]^[7] Its high oral bioavailability and brain penetration position it as a candidate for combinational therapies, though concerns over off-target effects—such as potential tumor promotion due to GSK-3β's role in cancer suppression—necessitate careful risk-benefit evaluation in broader applications.^[8]

Pharmacology

Mechanism of action

Tideglusib acts as a potent, irreversible, non-ATP competitive inhibitor of glycogen synthase kinase 3 beta (GSK-3β), with a time-dependent IC₅₀ of approximately 5 nM observed in cell-free assays after 60 minutes of preincubation. This inhibition pattern is characterized by a non-competitive relationship with ATP, as evidenced by kinetic studies showing a dissociation constant (K_i) of 60 nM and an α value of 22, indicating allosteric modulation rather than direct competition at the ATP-binding site. The irreversible nature is demonstrated by the absence of enzyme activity recovery upon dilution of unbound drug, with a near-zero dissociation rate constant (k₄ < 2.15 × 10⁻⁵ s⁻¹).^[9] At the molecular level, tideglusib binds within the active site of GSK-3β, specifically involving the cysteine residue Cys199, which facilitates the time-dependent and irreversible inhibition. This interaction disrupts GSK-3β's ability to phosphorylate key substrates, including tau protein at sites such as Ser396/404 and beta-catenin at Ser33/37/Thr41, thereby preventing downstream signaling events like tau aggregation and Wnt pathway suppression. Mutation of Cys199 to alanine (C199A) significantly reduces potency (IC₅₀ shifts to higher values) and allows partial reversibility, underscoring the residue's critical role, though direct evidence for covalent adduct formation remains inconclusive based on the lack of mass spectrometry confirmation and insensitivity to reducing agents like DTT.^[9]^[10] Tideglusib exhibits a selective inhibition profile, failing to significantly inhibit other kinases that lack a cysteine homologous to Cys199, such as cyclin-dependent kinase 5 (CDK5) and extracellular signal-regulated kinase 2 (ERK2), while also showing preferential activity against GSK-3β over GSK-3α (IC₅₀ ratio ≈ 10:1). Downstream, this selectivity translates to reduced tau hyperphosphorylation in preclinical Alzheimer's disease models, where tideglusib administration lowers phosphorylated tau levels and mitigates neurofibrillary tangle formation. In myotonic dystrophy models, GSK-3β inhibition by tideglusib normalizes aberrant RNA splicing patterns—such as those in BIN1, Serca1, and Cypher transcripts—through modulation of the GSK3β-CUGBP1 pathway, which enhances cellular maturation, reduces toxic CUG-expanded RNA foci, and improves myogenic differentiation without affecting overall RNA toxicity directly.^[9]^[11]^[12]

Pharmacokinetics

Tideglusib is administered orally, with clinical trials in myotonic dystrophy type 1 (DM1) utilizing once-daily doses of 400 mg or 1000 mg in adolescents and adults, often weight-banded or fixed to account for body size variations.^[13] Population pharmacokinetic analyses from these DM1 trials describe Tideglusib's disposition using a two-compartment model with first-order absorption and elimination, demonstrating linear pharmacokinetics across adolescent and adult populations with no significant accumulation upon repeated dosing.^[14] The terminal elimination half-life is approximately 1.7 to 2.0 hours, supporting daily administration without buildup, while the irreversible inhibition of its target enables sustained pharmacodynamic effects despite the short plasma half-life.^[13]^[9] Tideglusib likely undergoes hepatic metabolism involving cytochrome P450 3A4 (CYP3A4), as suggested by in vitro studies. Bioavailability is dose-dependent and high (approximately 88-100%), with area under the curve (AUC) values of approximately 1218 ng/mL·h at 400 mg and 3145 ng/mL·h at 1000 mg, reflecting solubility-limited absorption that can be influenced by food intake and decreases slightly at higher doses.^[14]^[15] No evidence of metabolic auto-inhibition or induction was observed in clinical pharmacokinetic evaluations.^[14] Distribution of Tideglusib is characterized by a central volume of distribution of about 154 L and a peripheral volume of 986 L, both scaled by body weight, facilitating broad tissue exposure.^[14] Its low molecular weight (334 Da) and lipophilic properties enable effective penetration of the blood-brain barrier, as demonstrated in rodent models where central nervous system effects were observed following systemic administration.^[16] Excretion occurs predominantly via the biliary route into feces following hepatic metabolism, with minimal renal clearance.^[17] The drug's safety profile includes transient, asymptomatic elevations in transaminases (primarily alanine aminotransferase) at higher doses, observed in approximately 9% of patients across trials and resolving upon discontinuation.^[3]

Chemistry

Structure and properties

Tideglusib is a synthetic small molecule with the molecular formula C₁₉H₁₄N₂O₂S.^[18] Its systematic IUPAC name is 4-benzyl-2-(naphthalen-1-yl)-1,2,4-thiadiazolidine-3,5-dione.^[1] The compound has a molar mass of 334.39 g/mol and appears as a white to off-white crystalline solid or powder.^[1]^[19] Key physical properties include low aqueous solubility, estimated at less than 0.01 mg/mL at physiological pH, which contributes to its classification as sparingly soluble in water.^[1] In contrast, it exhibits good solubility in organic solvents such as DMSO, exceeding 15 mg/mL with gentle warming.^[20] The calculated logP value of approximately 3.3 indicates moderate lipophilicity, facilitating its potential penetration across lipid membranes like the blood-brain barrier.^[1] Tideglusib demonstrates good stability when stored as a solid at -20°C, with a shelf life of at least 2–4 years under these conditions.^[21] It is known by development codes NP-12 and NP031112 and is registered in PubChem under CID 11313622.^[18]^[22]

Synthesis

Tideglusib, chemically known as 4-benzyl-2-(naphthalen-1-yl)-1,2,4-thiadiazolidine-3,5-dione, is synthesized via a cyclization reaction between benzyl isothiocyanate and 1-naphthyl isocyanate using sulfuryl chloride as the chlorinating agent.^[16] This one-pot process forms the central 1,2,4-thiadiazolidine-3,5-dione ring by promoting the addition and subsequent chlorination-dehydrochlorination steps.^[23] The reaction begins by dissolving equimolar amounts of benzyl isothiocyanate (13 mmol, 1.72 mL) and 1-naphthyl isocyanate (13 mmol, 1.9 mL) in hexane (50 mL) under a nitrogen atmosphere. Sulfuryl chloride (13 mmol, 1.04 mL) is added dropwise at 5°C to control the exothermic chlorination, followed by stirring at room temperature for 20 hours to complete the cyclization. The precipitated product is isolated by filtration and purified by recrystallization from ethanol, yielding 3.8 g (87%) of white needles with a melting point of 150°C.^[16] This method ensures high purity suitable for pharmaceutical applications, typically exceeding 98% after recrystallization.^[16] The starting isothiocyanate and isocyanate precursors are readily available or prepared in separate steps from the corresponding primary amines. For instance, benzyl isothiocyanate is generated by treating benzylamine with carbon disulfide (CS₂) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) in a solvent like dichloromethane, while 1-naphthyl isocyanate can be obtained via reaction of 1-naphthylamine with triphosgene. These preparatory steps, conducted at 0°C to room temperature, provide the intermediates in yields ranging from 37% to 84% depending on substituents, using flash chromatography for purification (petroleum ether to petroleum ether:ethyl acetate = 8:2).^[24] This synthesis is covered under US Patent 7,531,561 (Noscira Pharmaceuticals, 2009), which optimizes the route for efficient production of GSK-3 inhibitors.^[16] The mild conditions (non-aqueous solvents, low temperatures, no harsh catalysts beyond sulfuryl chloride) facilitate scalability for good manufacturing practice (GMP) production, though challenges include controlling side chlorination reactions during sulfuryl chloride addition and ensuring anhydrous conditions to prevent hydrolysis. Alternative oxidants like N-chlorosuccinimide have been explored for similar thiadiazolidinones to improve safety in larger-scale operations.^[25]

Clinical development

Early trials for neurodegenerative diseases

Tideglusib was discovered by Noscira Pharmaceuticals, a Spanish biotechnology company, in the early 2000s as a glycogen synthase kinase-3 (GSK-3) inhibitor targeting tau hyperphosphorylation in neurodegenerative conditions.^[26] The compound entered its first human trials between 2008 and 2010, with initial Phase I studies assessing safety in healthy volunteers followed by early Phase II investigations in patients with Alzheimer's disease (AD). Early clinical evaluation focused on AD, beginning with a Phase IIa pilot study in 2010 involving 30 patients with mild-to-moderate disease receiving escalating oral doses of 400 to 1000 mg over 20 weeks in a double-blind, placebo-controlled design.^[27] While no significant cognitive improvements were observed on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), the trial reported trends toward reduced brain atrophy on magnetic resonance imaging (MRI), suggesting potential neuroprotective effects despite the small sample size limiting statistical power.^[27] A subsequent pilot analysis published in 2013 reinforced these findings, noting biomarker improvements such as trends in reduced tau phosphorylation proxies alongside modest gains in cognitive scores (e.g., 4.72-point benefit on ADAS-Cog at highest doses), though not reaching significance.^[28] For progressive supranuclear palsy (PSP), Tideglusib received FDA Fast Track designation in 2010 to expedite development for this orphan indication.^[29] The pivotal Phase II TAUROS trial, completed in 2014, enrolled 146 patients with mild-to-moderate PSP randomized to 600 mg or 800 mg daily doses versus placebo for 52 weeks. The primary endpoint of improvement on the Progressive Supranuclear Palsy Rating Scale (PSPRS) showed no significant differences, but secondary analyses indicated trends toward stabilization of gait and cognition, with MRI evidence of slowed whole-brain atrophy progression, particularly in parietal and occipital regions. Across these trials, Tideglusib demonstrated a generally favorable safety profile, with most adverse events mild and comparable to placebo, including gastrointestinal effects such as nausea and diarrhea.^[28] Transient elevations in liver enzymes (ALT and AST) occurred more frequently in treated groups but were asymptomatic, reversible upon discontinuation, and resolved without long-term sequelae. Development for AD and PSP was halted by 2015 following the failure to meet key efficacy endpoints in these studies, prompting Noscira to shift resources and eventually leading to the asset's acquisition by AMO Pharma for alternative indications.^[30]

Current trials for myotonic dystrophy

Following the failure of tideglusib's initial development for Alzheimer's disease and progressive supranuclear palsy around 2015, AMO Pharma, a UK-based biotechnology company, repurposed the compound (as AMO-02) for congenital and juvenile-onset myotonic dystrophy type 1 (DM1), targeting GSK-3β inhibition to modulate RNA splicing defects associated with the disease.^[31]^[32] The REACH-CDM trial (NCT05004129), initiated in September 2021 and sponsored by AMO Pharma, was an open-label phase 2/3 study that enrolled up to 56 adolescents and young adults (aged 13-21 years) with congenital or juvenile-onset DM1 who completed a prior placebo-controlled study (NCT03692312).^[33] Completed in April 2023, the 52-week trial administered weight-adjusted oral doses of 400 mg, 600 mg, or 1000 mg once daily, with primary endpoints focused on the Clinician-Completed Congenital DM1 Rating Scale (CDM1-RS) for disease progression, alongside secondary measures of muscle strength via quantitative myometry (QMT), functional performance using the DM1-Activ scale, cognitive assessments, and safety monitoring.^[33]^[34] Interim data from the 2023 analysis, based on 48-week treatment in 56 participants, indicated that AMO-02 did not meet the primary endpoint of improving CDM1-RS scores compared to natural history expectations, but showed benefits in secondary outcomes, including enhanced grip strength as part of composite muscle strength measures, improved cognitive performance on the Peabody Picture Vocabulary Test (P < .05), better 10-meter walk/run times (P = .054), and reductions in creatine phosphokinase levels as a biomarker of muscle integrity (P < .05).^[34]^[35] The treatment was well-tolerated, with no treatment-related serious adverse events, no discontinuations due to adverse effects, and high retention (98% entering the optional extension, 85% completing one year); mild, expected transaminitis occurred but resolved without intervention, consistent with prior studies.^[34]^[35]^[36] An extension study, REACH-CDM-X, continued treatment for up to four years in participants from REACH-CDM. As of September 2025, long-term data from REACH-CDM-X highlighted a continued favorable safety profile for AMO-02, with no new safety signals, high tolerability, and no treatment-related serious adverse events reported over the extended period.^[6] Building on these findings, AMO Pharma announced plans in December 2020 for expanded phase 2/3 evaluation across DM1 phenotypes, with further progression to a dedicated phase 3 trial for adult-onset DM1 outlined in May 2024 following positive regulatory feedback.^[37] The U.S. FDA granted orphan drug designation for tideglusib in DM1 in June 2017, supporting accelerated development for this rare condition.^[38] AMO Pharma is scheduled to meet with the FDA in Q4 2025 to discuss the development plan for AMO-02 in congenital DM1.^[6] Dosing in the REACH-CDM trial employed daily oral administration to sustain GSK-3β inhibition, leveraging tideglusib's irreversible binding mechanism, which allows for less frequent dosing than reversible inhibitors while achieving steady-state effects; liver enzyme levels (ALT/AST) are routinely monitored due to potential transaminitis, with dose adjustments if elevations exceed predefined thresholds.^[33]^[36]

Research

Regenerative applications

Tideglusib has demonstrated preclinical potential in promoting dental tissue repair through inhibition of glycogen synthase kinase-3β (GSK-3β), which activates the Wnt/β-catenin signaling pathway to stimulate odontoblast-like cell differentiation and tertiary dentin formation. In mouse models of tooth injury, low-dose Tideglusib (50 nM delivered via collagen sponge) induced complete reparative dentin formation that bridged injury sites and preserved vital dental pulp after 6 weeks, with mineralization levels approximately twice that of controls and 1.7 times higher than mineral trioxide aggregate (MTA).^[39] This localized application suggests Tideglusib's viability as a non-invasive treatment for dental caries, potentially revolutionizing pulp protection by leveraging endogenous stem cell renewal without invasive procedures.^[39] In preclinical models of myotonic dystrophy type 1 (DM1), Tideglusib supports neuromuscular regeneration by normalizing muscle maturation and alleviating pathological phenotypes through GSK-3β inhibition. Studies in the HSA^LR mouse model of DM1 revealed that early GSK-3β inhibition prevented muscle pathology development, reduced myotonia, and improved muscle weakness by correcting dysregulated cyclin D3 levels and enhancing myoblast differentiation.^[40] Similarly, in the DMSXL DM1 mouse model, Tideglusib treatment reduced toxic DMPK mRNA accumulation, improved postnatal survival, growth, and neuromotor activity, thereby providing foundational evidence for its translation to DM1 therapeutics.^[32] The potential off-label use of Tideglusib in dentistry raises ethical considerations centered on patient autonomy, beneficence, and regulatory oversight. Informed consent must clearly convey risks such as potential tumorigenesis or teratogenicity, avoiding media-driven hype that may mislead patients on safety profiles.^[41] While Phase 0-like preclinical reevaluations of molecular pathways and risks have been proposed to bridge gaps before human trials, no advanced studies have materialized, emphasizing the need for rigorous Phase III/IV trials to align dental applications with clinical medicine standards.^[41] Tideglusib's regenerative effects exhibit dose-dependency, with low concentrations (e.g., 50 nM) promoting repair while higher doses induce cytotoxicity and suppress outcomes. In vitro assessments on human fibroblasts demonstrated that Tideglusib viability decreases progressively above 31.25 nM, leading to cell death and inflammatory responses that could hinder tissue regeneration in dental or neuromuscular contexts.^[42] This limitation underscores the importance of precise dosing to avoid counterproductive suppression of proliferative and reparative processes.

Oncological potential

Tideglusib has demonstrated preclinical anti-cancer potential primarily through its irreversible inhibition of glycogen synthase kinase-3β (GSK-3β), a kinase implicated in tumor cell survival and proliferation pathways. In human neuroblastoma IMR-32 cells, treatment with 5-10 μM Tideglusib induces apoptosis by activating caspases and disrupting mitochondrial integrity via GSK-3β-dependent mechanisms, leading to reactive oxygen species generation and sub-G0/G1 cell cycle arrest.^[43] In ovarian teratocarcinoma-derived PA-1 cells, Tideglusib inhibits cell proliferation and colony formation in vitro at micromolar concentrations, while synergizing with chemotherapeutic agents such as cisplatin to enhance cytotoxicity through disruption of β-catenin signaling and promotion of apoptotic pathways. This effect underscores its role in targeting Wnt/β-catenin-driven oncogenesis, a common feature in gynecological malignancies.^[44] Beyond these models, Tideglusib exhibits activity against other GSK-3β-dependent cancers, including glioblastoma multiforme, where it reduces proliferation, migration, and stem-like properties in U87 and U251 cell lines, particularly when combined with radiation therapy to sensitize cancer stem cells. Preclinical studies in rhabdomyosarcoma xenografts further highlight its on-target GSK-3β inhibition but note limited single-agent efficacy against tumor growth. As of November 2025, no clinical trials evaluating Tideglusib for oncological indications have been initiated, with research remaining confined to in vitro and murine models.^[45]^[46] Although primarily explored for neurodegenerative conditions, Tideglusib's neuroprotective effects have prompted proposed repurposing for amyotrophic lateral sclerosis (ALS), where oral administration (200 mg/kg daily) reduced TDP-43 phosphorylation in the Prp-hTDP-43^(A315T) mouse model via GSK-3β inhibition. As of November 2025, a Phase 1 trial (NCT05105958) is evaluating its safety and tolerability in ALS patients. In oncology contexts, achieving anti-tumor effects often requires higher micromolar doses in vitro, which may translate to elevated systemic exposure and narrow the therapeutic window due to potential off-target inhibition of related kinases, as observed in tolerability studies across cancer models.^[47]^[48]

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