| Size | Price | |
|---|---|---|
| 500mg | ||
| 1g | ||
| Other Sizes |
Purity: ≥98%
| Targets |
Beta-secretase 1 (BACE1), with a Ki of 0.4 nM; inhibits the cleavage of amyloid precursor protein (APP), preventing the production of amyloid-β peptides.
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| ln Vitro |
AZD3293 is a potent, highly permeable, orally active, blood-brain barrier (BBB) penetrating, BACE1 inhibitor with unique slow off-rate kinetics. When the potency of AZD3293 with respect to secretion of Aβ40 and sAβPPβ is studied in a range of cellular models, the compound displays pM potency in primary neuron cultures from mice and guinea pigs and in SH-SY5Y cells over-expressing AβPP (IC50 = 610 pM, 310 pM, and 80 pM, respectively). AZD3293 is also tested in a panel of more than 350 in vitro radioligand binding and enzyme activity assays, covering a diverse range of receptors, ion channels, transporters, kinases, and enzymes, up to a concentration of 10μM of AZD3293. A few significant responses are observed, but these had at least a 1,000-fold selectivity against BACE1, thus indicating specificity to BACE1. The off-rate of AZD3293 has an estimated t1/2 of approximately 9 h.
Kinase Assay: Lanabecestat (formerly known as AZD3293 and LY3314814), is a novel potent, orally bioactive, highly permeable, brain-penetreable inhibitor of beta-secretase 1 cleaving enzyme (BACE) with a Ki of 0.4 nM. AZD3293 displayed significant dose- and time-dependent reductions in plasma, cerebrospinal fluid, and brain concentrations of Aβ40, Aβ42, and sAβPPβ. Cell Assay: The cells [SH-SY5Y, SH-SY5Y overexpressing wild type AβPP, HEK293 cells overexpressing AβPP with the Swedish mutation (K595N/M596L), N2A cells, and primary cortical neurons isolated from fetal C57BL/6 mice (E16) or Dunkin-Hartley guinea pigs (E25-27)] are incubated with different AZD3293 concentrations for 5 to 16 h, and the release of sAβPPβ, Aβ1-40, Aβ1-42, or sAβPPα into the medium is analyzed using specific commercial ELISA or kits from Meso Scale Discovery. Lanabecestat potently inhibits BACE1 (Ki=0.4 nM); it reduces amyloid-β production and has the potential to slow the progression of Alzheimer's disease by preventing amyloid plaque formation. |
| ln Vivo |
In vivo in mice, guinea pigs, and dogs, AZD3293 displays significant dose- and time-dependent reductions in plasma, cerebrospinal fluid, and brain concentrations of Aβ40, Aβ42, and sAβPPβ. In the dog PK study, the bioavailability of AZD3293 is determined to be 80% (F = 0.8). The preclinical data strongly support the clinical development of AZD3293, and patients with AD are currently being recruited into a combined Phase 2/3 study to test the disease-modifying properties of AZD3293.
In vivo, lanabecestat lowers brain Aβ levels in preclinical models and has been investigated in clinical trials for Alzheimer's disease; it is orally active and brain-penetrant. |
| Enzyme Assay |
BACE1 activity is measured using a fluorescence-based or radiometric assay with recombinant BACE1 and a substrate peptide; inhibition is quantified by measuring cleavage product formation in the presence of the compound.
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| Cell Assay |
Cells expressing APP are treated with lanabecestat; Aβ40 and Aβ42 levels in the conditioned medium are measured by ELISA to assess BACE1 inhibition.
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| Animal Protocol |
Formulated in 5% dimethylacetamide in 0.3 M gluconic acid, pH 3; 50, 100, or 200μmol/kg; p.o.C57BL/6 mice
In vivo efficacy is evaluated in transgenic mouse models of Alzheimer's disease; brain Aβ levels, plaque burden, and cognitive function are assessed following oral administration. |
| References |
J Alzheimers Dis.2016;50(4):1109-23.
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| Molecular Formula |
C36H44N4O5S
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|---|---|---|
| Molecular Weight |
644.83
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| Exact Mass |
644.303
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| CAS # |
1522418-41-2
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| Related CAS # |
1383986-31-9 (HCl);1383982-64-6;1628076-74-3 (deleted);1522418-41-2 (camsylate);
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| PubChem CID |
137091139
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| Appearance |
Typically exists as solid at room temperature
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| LogP |
6.157
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
46
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| Complexity |
1230
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| Defined Atom Stereocenter Count |
2
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| SMILES |
S(CC12C(CC(CC1)C2(C)C)=O)(=O)(=O)O.O(C)C1CCC2(CC3C=CC(C4C=NC=C(C#CC)C=4)=CC=3[C@@]32N=C(C(C)=N3)N)CC1
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| InChi Key |
PEOILZBROWEGCC-GWKIJFMESA-N
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| InChi Code |
InChI=1S/C26H28N4O.C10H16O4S/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;1-9(2)7-3-4-10(9,8(11)5-7)6-15(12,13)14/h6-7,12-13,15-16,22H,8-11,14H2,1-3H3,(H2,27,30);7H,3-6H2,1-2H3,(H,12,13,14)/t22?,25?,26-;7?,10-/m01/s1
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| Synonyms |
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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 |
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| 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) |
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| Solubility (In Vivo) |
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| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.5508 mL | 7.7540 mL | 15.5080 mL | |
| 5 mM | 0.3102 mL | 1.5508 mL | 3.1016 mL | |
| 10 mM | 0.1551 mL | 0.7754 mL | 1.5508 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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