| Size | Price | Stock | Qty |
|---|---|---|---|
| 10mg |
|
||
| 25mg |
|
||
| 50mg |
|
||
| 100mg | |||
| 250mg | |||
| Other Sizes |
Purity: ≥98%
| Targets |
BACE1 (Ki = 0.4 nM; IC50 = 0.6 nM in vitro)
|
|---|---|
| ln Vitro |
With a competitive and reversible mode of action towards the hBACE1 active site, lanabecestat functions as a complete inhibitor of BACE1 in vitro. Lanabecestat exhibits a notably slow target off-rate along with a very high target affinity. The estimated t1/2 of lanabecestat's off-rate is roughly 9 hours. In primary neuron cultures from mice and guinea pigs as well as in SH-SY5Y cells that overexpress AβPP, lanabecestat exhibits pM potency (IC50=610 pM, 310 pM, and 80 pM, respectively). Using mouse, rat, guinea pig, dog, and human plasma, equilibrium dialysis is used to determine the in vitro plasma protein binding of lanabecestat. For the length of the in vitro incubation period, at least, the compound remains stable in the plasma of these species. For mice, the unbound fractions are 1.3% to 1.8%, for rats, 4.2% to 5.9%, for guinea pigs, 8.3% to 10.3%, for dogs, 9.4% to 10.3%, and for human plasma, 7.7% to 9.4%. Human blood's mean blood:plasma ratio of 0.7 shows no discernible relationship to red blood cells. In the brain tissue binding assay, the free fraction is 4.5%[1].
AZD3293 demonstrates high potency against BACE1 with a Ki of 0.4 nM and an IC50 of 0.6 nM in vitro. It also inhibits BACE2 with an IC50 of 0.9 nM. The compound shows high selectivity over hCathepsin D (IC50 = 16,100 nM) and hERG (IC50 = 4,700 nM). In primary cortical neurons, AZD3293 inhibits Aβ40 secretion with IC50 values of 0.61 nM (mouse) and 0.31 nM (guinea pig). In SH-SY5Y cells overexpressing human APP, the IC50 is 0.08 nM. The slow off-rate from BACE1 (t1/2 ≈ 9 hours) translates into prolonged on-target effects beyond the turnover rate of Aβ, enabling once-weekly dosing. |
| ln Vivo |
Lanabecestat shows notable dose- and time-dependent decreases in the concentrations of Aβ40, Aβ42, and sAβPPβ in the brain, cerebrospinal fluid, and plasma in mice, guinea pigs, and dogs[1].
In vivo, AZD3293 displays significant dose- and time-dependent reductions in plasma, cerebrospinal fluid, and brain concentrations of Aβ40, Aβ42, and sAβPPβ in mice, guinea pigs, and dogs. In mice, doses of 50, 100, and 200 µmol/kg reduce plasma and brain Aβ40 and brain Aβ42 levels. The slow off-rate from BACE1 (t1/2 ≈ 9 hours) translates into prolonged on-target effects beyond the turnover rate of Aβ. The compound's ability to reduce Aβ levels in the brain and CSF has been confirmed in multiple preclinical species and in human clinical trials. |
| Enzyme Assay |
BACE1 enzyme activity is measured using FRET-based assays with synthetic peptide substrates. IC50 values are determined from dose-response curves. Radioligand binding assays are used to determine Ki values. Selectivity profiling is conducted against BACE2, cathepsin D, γ-secretase, and hERG. Off-rate kinetics are measured using dilution or competition binding assays to determine the slow dissociation rate (t1/2 ≈ 9 hours).
|
| Cell Assay |
Cellular potency is assessed in primary cortical neurons from mice and guinea pigs, and in SH-SY5Y cells overexpressing human APP. Cells are incubated with different AZD3293 concentrations for 5–16 hours, and the release of sAβPPβ, Aβ1-40, Aβ1-42, or sAβPPα into the medium is analyzed using ELISA or specific kits. Cytotoxicity is evaluated using cell proliferation/cytotoxicity kits. The compound's ability to inhibit Aβ secretion in neurons confirms its cellular activity.
|
| Animal Protocol |
Formulated in 5% dimethylacetamide in 0.3 M gluconic acid, pH 3; 50, 100, or 200μmol/kg; p.o.
C57BL/6 mice Female 7- to 14-week-old C57BL/6 mice receive vehicle or AZD3293 at 50, 100, or 200 µmol/kg as a single oral dose. Mice and guinea pigs are anesthetized at various time points (1.5–48 hours post-dose), CSF is aspirated from the cisterna magna, and plasma and brain tissues are collected. Aβ40, Aβ42, and sAβPPβ levels are measured in plasma, CSF, and brain homogenates. The compound's ability to reduce Aβ levels in the brain and CSF has been confirmed in multiple preclinical species. |
| ADME/Pharmacokinetics |
AZD3293 is a substrate of CYP3A4, and plasma concentrations may be increased up to 3-fold in the presence of strong CYP3A4 inhibitors like itraconazole. The compound is highly permeable and brain-penetrant. In Phase 1 studies, AZD3293 demonstrates dose-dependent pharmacokinetics with prolonged suppression of plasma Aβ, enabling once-weekly dosing. Detailed PK parameters including Cmax, AUC, half-life, and bioavailability are available from multiple clinical studies in healthy subjects and Alzheimer's patients.
|
| Toxicity/Toxicokinetics |
AZD3293 has been evaluated in extensive clinical trials including Phase 2/3 studies (AMARANTH, NCT02245737). The AMARANTH trial was deemed futile as treatment did not change cognitive outcomes despite reducing β-amyloid. Safety data from clinical trials show that the compound is generally well-tolerated, though some cognitive worsening was observed on certain assessments. Comprehensive toxicology data are available from the clinical development program.
|
| References | |
| Additional Infomation |
Lanabecestat is being studied in the clinical trial NCT03499041 (LY3314814 study in patients with impaired liver function).
AZD3293 was developed by AstraZeneca and Eli Lilly as a disease-modifying BACE1 inhibitor for Alzheimer's disease. It is the only BACE1 inhibitor for which prolonged suppression of plasma Aβ with a once-weekly dosing schedule has been reported. Despite reducing β-amyloid levels, the compound failed to show cognitive benefit in Phase 2/3 trials, leading to discontinuation of development. It remains a valuable tool compound for studying BACE1 biology and amyloid pathology. The compound was investigated in three Phase 3 trials (NCT02245737, NCT02783573, and NCT02972658) at daily doses of 20 and 50 mg. |
| Molecular Formula |
C26H28N4O
|
|
|---|---|---|
| Molecular Weight |
412.53
|
|
| Exact Mass |
412.226
|
|
| CAS # |
1383982-64-6
|
|
| Related CAS # |
(1α,1'S,4β)-Lanabecestat;1384082-96-5
|
|
| PubChem CID |
67979346
|
|
| Appearance |
White to off-white solid powder
|
|
| Density |
1.2±0.1 g/cm3
|
|
| Boiling Point |
621.9±65.0 °C at 760 mmHg
|
|
| Flash Point |
329.9±34.3 °C
|
|
| Vapour Pressure |
0.0±1.8 mmHg at 25°C
|
|
| Index of Refraction |
1.656
|
|
| LogP |
3.02
|
|
| Hydrogen Bond Donor Count |
1
|
|
| Hydrogen Bond Acceptor Count |
4
|
|
| Rotatable Bond Count |
3
|
|
| Heavy Atom Count |
31
|
|
| Complexity |
827
|
|
| Defined Atom Stereocenter Count |
1
|
|
| SMILES |
CC#CC1=CC(=CN=C1)C2=CC3=C(CC4([C@]35N=C(C(=N5)N)C)CCC(CC4)OC)C=C2
|
|
| InChi Key |
WKDNQONLGXOZRG-BOPKNSRXSA-N
|
|
| 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-/m0/s1
|
|
| Synonyms |
|
|
| HS Tariff Code |
2934.99.9001
|
|
| 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)
|
| Solubility (In Vitro) |
|
|||
|---|---|---|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.06 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 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 25.0 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. Solubility in Formulation 2: ≥ 2.5 mg/mL (6.06 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (6.06 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: ≥ 2.5 mg/mL (6.06 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 5: ≥ 2.5 mg/mL (6.06 mM) (saturation unknown) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 6: 0.5 mg/mL (1.21 mM) in 1% DMSO 99% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. |
| 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.
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
COA