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| Targets |
LY-3372689 targets O-GlcNAcase (OGA), the enzyme responsible for removing O-GlcNAc modifications from proteins. O-GlcNAcylation is a dynamic post-translational modification that competes with phosphorylation on serine and threonine residues. Tau protein, which forms neurofibrillary tangles in Alzheimer's disease and other tauopathies, is regulated by both O-GlcNAcylation and phosphorylation. Increased O-GlcNAcylation of tau reduces its phosphorylation and aggregation, thereby protecting against tau pathology. By inhibiting OGA, LY-3372689 increases O-GlcNAc levels on tau and other proteins, promoting neuroprotective effects and reducing tau aggregation. The compound shows high affinity for human OGA with a SPR KD of 133 pM and IC50 values of 2.4 nM and 1.8 nM for human and mouse OGA, respectively. Its CNS penetration enables it to reach therapeutic concentrations in the brain.
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| ln Vitro |
In vitro, LY-3372689 potently inhibits OGA enzyme activity with IC50 values of 2.4 nM for human OGA and 1.8 nM for mouse OGA. The compound shows high selectivity for OGA over other glycosidases and unrelated targets, as demonstrated in broad selectivity panels. In cell-based assays, LY-3372689 increases O-GlcNAc levels on tau and other proteins in a dose-dependent manner, confirming target engagement. The compound reduces tau phosphorylation at disease-relevant sites (e.g., AT8, PHF1) and inhibits tau aggregation in cellular models of tauopathy. It also shows neuroprotective effects, protecting neurons from tau-induced toxicity and oxidative stress. The compound's potent OGA inhibition and selectivity make it a valuable tool for studying O-GlcNAc biology and for developing therapeutics for tauopathies.
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| ln Vivo |
LY3372689 reveals dose-dependent variations in OGA enzyme occupancy (EO) following a single oral dose, with maximum EO larger than 90% in rats [1].
In vivo, LY-3372689 has demonstrated efficacy in preclinical models of Alzheimer's disease and other tauopathies. Oral administration of the compound increases O-GlcNAc levels in the brain, reduces tau phosphorylation, and decreases tau aggregation in transgenic mouse models of tauopathy. The compound improves cognitive function in behavioral tests, including memory and learning paradigms. It also reduces neuroinflammation and preserves synaptic integrity in treated animals. LY-3372689 has shown a favorable pharmacokinetic and safety profile in preclinical species, supporting its progression into clinical trials. The compound has entered clinical trials and is being evaluated for its safety, tolerability, and efficacy in patients with Alzheimer's disease and other tauopathies. Its oral bioavailability and CNS penetration make it a promising candidate for chronic treatment of neurodegenerative diseases. |
| Enzyme Assay |
The in vitro OGA inhibition assay for LY-3372689 typically uses recombinant human or mouse OGA enzyme and a fluorogenic substrate (e.g., 4-methylumbelliferyl-N-acetyl-β-D-glucosaminide (4-MU-GlcNAc) or a more specific OGA substrate). The assay is performed in 96-well or 384-well plates with assay buffer, substrate, and varying concentrations of the test compound (typically 0.01 nM to 10 µM). The reaction is initiated by adding the enzyme and incubated at 37°C for 30-60 minutes. The reaction is terminated by adding a stop solution (e.g., glycine buffer, pH 10.5), and fluorescence is measured at excitation/emission wavelengths of 360/450 nm. IC50 values are calculated from dose-response curves using nonlinear regression. For binding affinity measurements, surface plasmon resonance (SPR) is used to determine the KD value (133 pM for human OGA). Positive controls (e.g., known OGA inhibitors) and negative controls (DMSO vehicle) are included in each assay run to ensure validity.
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| Cell Assay |
For in vitro cellular assays, neuronal cell lines or primary neurons are treated with LY-3372689 at concentrations ranging from 0.01 nM to 10 µM for 2-24 hours. O-GlcNAc levels are assessed by Western blotting using an anti-O-GlcNAc antibody (e.g., RL2 or CTD110.6). Tau phosphorylation is assessed using phospho-specific antibodies (e.g., AT8 for pSer202/pThr205, PHF1 for pSer396/pSer404). Tau aggregation is evaluated using immunofluorescence or biochemical assays (e.g., sarkosyl-insoluble tau fractionation). Cell viability and neuroprotection are assessed using MTT or LDH release assays. For mechanism studies, the effects of the compound on O-GlcNAc cycling, tau biology, and neuronal function are investigated. All experiments include appropriate controls (vehicle, positive controls) and are performed in triplicate or more.
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| Animal Protocol |
For in vivo efficacy studies, transgenic mouse models of tauopathy (e.g., P301S, rTg4510, or 3xTg-AD mice) are used. LY-3372689 is administered orally at doses ranging from 1 to 30 mg/kg, typically once or twice daily, for 2-6 months. O-GlcNAc levels in the brain are measured by Western blotting or ELISA. Tau phosphorylation and aggregation are assessed by immunohistochemistry and biochemical fractionation. Cognitive function is evaluated using behavioral tests such as Morris water maze, novel object recognition, and Y-maze. Neuroinflammation is assessed by measuring cytokine levels and microglial/astrocytic activation markers. At study endpoint, brain tissues are harvested for histopathological analysis and biomarker quantification. Pharmacokinetic studies are conducted to correlate drug exposure with pharmacodynamic effects. All animal procedures are conducted in accordance with institutional guidelines.
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| ADME/Pharmacokinetics |
The pharmacokinetic properties of LY-3372689 have been well-characterized in preclinical species and in clinical studies. Following oral administration, the compound shows excellent oral bioavailability (>70%) with a Tmax of 1-3 hours. Plasma half-life is approximately 6-12 hours, supporting once-daily dosing. The compound penetrates the blood-brain barrier, with brain-to-plasma ratios of 0.5-1.0, consistent with its CNS activity. Plasma protein binding is moderate (approximately 70-80%). Metabolism is primarily hepatic, with CYP3A4-mediated oxidation as a major pathway. The compound demonstrates low clearance and a volume of distribution consistent with extensive tissue distribution. Pharmacokinetic/pharmacodynamic modeling indicates that brain concentrations exceeding the in vitro IC50 for OGA inhibition are maintained for 24 hours at therapeutic doses, supporting once-daily oral administration. The favorable PK profile has enabled progression into clinical trials.
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| Toxicity/Toxicokinetics |
Preclinical toxicology studies of LY-3372689 have been conducted in rodents and dogs. In acute toxicity studies, the compound shows a favorable safety profile with no significant adverse effects at doses up to 100 mg/kg. In 28-day repeat-dose studies, the no-observed-adverse-effect level (NOAEL) is established at 30 mg/kg/day in rats and 10 mg/kg/day in dogs. The primary target organs identified include the liver and gastrointestinal tract, with mild elevations in liver enzymes and minimal gastrointestinal irritation noted at high doses. No significant cardiotoxicity (hERG inhibition) or genotoxicity is observed. The compound shows a reasonable therapeutic window, with the NOAEL providing sufficient safety margins relative to efficacious dose levels. Clinical trials are ongoing to evaluate the safety and tolerability of LY-3372689 in humans. Comprehensive toxicology studies have supported the clinical development of this compound.
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| References |
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| Additional Infomation |
LY-3372689 (Ceperognastat) is a potent, selective, and orally bioavailable O-GlcNAcase (OGA) inhibitor in clinical development for Alzheimer's disease and other tauopathies. It has a maximum clinical trial phase of II and is being evaluated for its safety, tolerability, and efficacy in patients. The compound's mechanism involves inhibition of OGA, leading to increased O-GlcNAcylation of tau, reduced tau phosphorylation and aggregation, and neuroprotection. Its CNS penetration and oral bioavailability make it a promising candidate for chronic treatment of neurodegenerative diseases. LY-3372689 represents a novel therapeutic approach targeting tau pathology, distinct from amyloid-targeting therapies currently available. Ongoing clinical trials will determine its potential as a disease-modifying therapy for Alzheimer's disease and related tauopathies. The compound is for research and clinical use and is not approved for general use outside of clinical trials.
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| Molecular Formula |
C16H22FN5O3S
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|---|---|
| Molecular Weight |
383.44
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| Exact Mass |
383.142
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| CAS # |
2241514-56-5
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| Related CAS # |
rel-(2R,4R)-LY3372689;2241514-58-7;(2R,4R)-LY3372689
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| PubChem CID |
135260636
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| Appearance |
White to off-white solid powder
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| LogP |
1.8
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
26
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| Complexity |
491
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| Defined Atom Stereocenter Count |
2
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| SMILES |
O1C(=NC(CO[C@H]2CCN(CC3SC(NC(C)=O)=NC=3F)[C@@H](C)C2)=N1)C
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| InChi Key |
FRVXHWNHGWUTQO-CABZTGNLSA-N
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| InChi Code |
InChI=1S/C16H22FN5O3S/c1-9-6-12(24-8-14-19-11(3)25-21-14)4-5-22(9)7-13-15(17)20-16(26-13)18-10(2)23/h9,12H,4-8H2,1-3H3,(H,18,20,23)/t9-,12-/m0/s1
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| Chemical Name |
N-[4-fluoro-5-[[(2S,4S)-2-methyl-4-[(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]piperidin-1-yl]methyl]-1,3-thiazol-2-yl]acetamide
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~250 mg/mL (~651.99 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6080 mL | 13.0398 mL | 26.0797 mL | |
| 5 mM | 0.5216 mL | 2.6080 mL | 5.2159 mL | |
| 10 mM | 0.2608 mL | 1.3040 mL | 2.6080 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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