| Size | Price | Stock | Qty |
|---|---|---|---|
| 5mg |
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| 10mg |
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| 50mg | |||
| Other Sizes |
| Targets |
BACE1
The primary target of Lanabecestat is beta-secretase 1 (BACE1), the rate-limiting enzyme in the production of amyloid-beta (Abeta) peptides. Lanabecestat is a potent, highly permeable, orally active, and blood-brain barrier penetrating BACE1 inhibitor with unique slow off-rate kinetics. It has a Ki of 0.4 nM for BACE1 and reduces the production of Abeta species from amyloid precursor protein (APP). It also inhibits BACE2, but BACE1 is the primary therapeutic target for Alzheimer‘s disease. |
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| ln Vitro |
In vitro, Lanabecestat (AZD3293) is a potent BACE1 inhibitor with a Ki of 0.4 nM. It is highly permeable and effectively penetrates cells and the blood-brain barrier (BBB). The compound has unique slow off-rate binding kinetics, meaning that once it binds to BACE1, it dissociates slowly, resulting in sustained target inhibition and prolonged pharmacodynamic effects. This slow off-rate contributes to its potent and long-lasting reduction of Abeta production.
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| ln Vivo |
In vivo, Lanabecestat is an orally active, brain-permeable BACE1 inhibitor that reduces Abeta production in mouse, guinea pig, and dog in a time- and dose-dependent manner. It significantly reduces soluble Abeta species and soluble amyloid precursor proteins (sAPPbeta) in cerebrospinal fluid (CSF) and brain tissue. Lanabecestat progressed to Phase III clinical trials for the treatment of Alzheimer‘s disease, with daily doses of 20 and 50 mg, before being discontinued due to lack of efficacy on cognitive endpoints.
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| Enzyme Assay |
The non-cellular activity of Lanabecestat is measured using a fluorescence resonance energy transfer (FRET)-based BACE1 enzyme assay. Recombinant human BACE1 enzyme is incubated with a fluorescent peptide substrate (e.g., APPsw substrate conjugated to EDANS and DABCYL) and varying concentrations of Lanabecestat (0.001-10 uM) in assay buffer (50 mM sodium acetate, pH 4.5). After incubation at room temperature for 60-90 minutes, fluorescence is measured (excitation 355 nm, emission 485 nm). The IC50 is calculated, and Ki (0.4 nM) is determined using the Cheng-Prusoff equation.
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| Cell Assay |
For cellular assays, BACE1-expressing cells (e.g., HEK-293 cells overexpressing human APP with the Swedish mutation, or primary cortical neurons) are treated with Lanabecestat (0.01-10 uM) for 24 hours. The levels of secreted Abeta40 and Abeta42 in the cell culture medium are quantified by ELISA. The compound concentration that reduces Abeta production by 50% (IC50) is calculated from the dose-response curve. This cellular potency reflects the compound's ability to inhibit BACE1 in a more physiologically relevant environment.
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| Animal Protocol |
In an in vivo protocol, male or female APP transgenic mice (e.g., PDAPP, Tg2576, or APP/PS1 mice) or wild-type rodents (rats or guinea pigs) are used. Lanabecestat is administered orally (e.g., 0.1-30 mg/kg) in a suitable vehicle (e.g., 0.5% methylcellulose or 10% DMSO/60% PEG400/30% water). At various time points (1, 3, 6, 12, 24 hours) after dosing, animals are euthanized. Cerebrospinal fluid (CSF) is collected from the cisterna magna, and brain tissue is dissected. Levels of Abeta40 and Abeta42 in CSF and brain homogenates are measured by ELISA. The reduction in CSF and brain Abeta levels relative to vehicle control indicates target engagement and pharmacodynamic activity.
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| ADME/Pharmacokinetics |
Lanabecestat is described as having a unique slow off-rate kinetic profile, which contributes to prolonged target inhibition and sustained reduction of Abeta. It is highly permeable, orally active, and penetrates the blood-brain barrier. Specific pharmacokinetic parameters (t1/2, Cmax, oral bioavailability) were established in preclinical and clinical studies but are not provided in detail in these references. In clinical trials, daily doses of 20 and 50 mg were used, suggesting that the compound has sufficient half-life and exposure for once-daily oral administration.
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| Toxicity/Toxicokinetics |
No detailed toxicological data is provided in these references, but Lanabecestat was advanced to Phase III clinical trials, indicating that it had an acceptable safety profile in preclinical and early clinical studies. Common adverse effects associated with BACE1 inhibitors may include cutaneous and ophthalmologic findings (hair discoloration, skin rash, lenticular changes) due to off-target BACE2 inhibition. The compound was generally safe and well-tolerated in Phase I studies, though the Phase III program was discontinued due to lack of efficacy on cognitive endpoints rather than toxicity.
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| References | |
| Additional Infomation |
Lanabecestat (AZD3293, LY3314814) is a BACE1 inhibitor developed by AstraZeneca and Eli Lilly for the treatment of Alzheimer‘s disease. It represents one of several BACE1 inhibitors that reached late-stage clinical trials (Phase III) and was one of the most advanced compounds in this drug class. The development of Lanabecestat was discontinued in 2018 after an independent data monitoring committee concluded that the Phase III trials were unlikely to meet their primary cognitive endpoints, despite robust Abeta reduction in CSF. The failure of Lanabecestat and other BACE1 inhibitors (verubecestat, atabecestat, umibecestat) raised important questions about the Abeta hypothesis and the therapeutic potential of BACE1 inhibition for Alzheimer's disease. The (1alpha,1‘S,4beta) stereoisomer is the specific active enantiomer of the compound, though racemic mixtures are also available for research. Lanabecestat is a valuable reference compound for studying BACE1 pharmacology and the role of Abeta in AD pathogenesis.
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| Molecular Formula |
C26H28N4O
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|---|---|
| Molecular Weight |
412.5267
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| Exact Mass |
412.226
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| CAS # |
1384082-96-5
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| Related CAS # |
Lanabecestat;1383982-64-6
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| PubChem CID |
67979371
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| Appearance |
Light yellow to khaki solid powder
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| LogP |
3
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
31
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| Complexity |
827
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| Defined Atom Stereocenter Count |
1
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| SMILES |
O(C([H])([H])[H])C1([H])C([H])([H])C([H])([H])C2(C([H])([H])C3C([H])=C([H])C(C4=C([H])N=C([H])C(C#CC([H])([H])[H])=C4[H])=C([H])C=3[C@]32N=C(C(C([H])([H])[H])=N3)N([H])[H])C([H])([H])C1([H])[H]
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| InChi Key |
WKDNQONLGXOZRG-TXDAUAKNSA-N
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| InChi Code |
InChI=1S/C26H28N4O/c1-4-5-18-12-21(16-28-15-18)19-6-7-20-14-25(10-8-22(31-3)9-11-25)26(23(20)13-19)29-17(2)24(27)30-26/h6-7,12-13,15-16,22H,8-11,14H2,1-3H3,(H2,27,30)/t22?,25?,26-/m1/s1
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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 (606.02 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.17 mg/mL (5.26 mM) (saturation unknown) in 10% DMSO + 40% PEG300 +5% Tween-80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 21.7 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 + to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4241 mL | 12.1203 mL | 24.2407 mL | |
| 5 mM | 0.4848 mL | 2.4241 mL | 4.8481 mL | |
| 10 mM | 0.2424 mL | 1.2120 mL | 2.4241 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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