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In vitro: Lanabecestat (AZD3293, LY3314814) 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.
In 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
| Cell Experiment | |
|---|---|
| Cell lines | 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) |
| Preparation method | The cells 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. |
| Concentrations | |
| Incubation time | 5 to 16 h |
| Animal Experiment | |
|---|---|
| Animal models | C57BL/6 mice |
| Formulation | 5% dimethylacetamide in 0.3 M gluconic acid, pH 3 |
| Dosages | 50, 100, or 200μmol/kg |
| Administration | oral administration |
| Molecular Weight | 412.53 |
| Formula | C26H28N4O |
| CAS Number | 1383982-64-6 |
| Solubility (25°C) | 82 mg/mL in DMSO |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Related BACE Products |
|---|
| LY2886721
LY2886721 is an effective, selective, orally active inhibitor of beta-site amyloid precursor protein lyase 1 (BACE1) with an IC50 of 20.3 nM against recombinant human BACE1. LY2886721 showed higher selectivity for BACE1 than cathepsin D, pepsin and renin, but lacked selectivity for BACE2 (IC50 was 10.2 nM). LY2886721 crosses the blood-brain barrier and can be used to study Alzheimer's disease. |
| AZD3839
AZD3839 is a potent and selective inhibitor of human BACE1 with Ki of 26.1 nM. |
| Eslicarbazepine Acetate
Eslicarbazepine acetate is an antiepileptic drug. |
| Verubecestat (MK-8931)
Verubecestat (MK-8931) is an orally active, high-affinity (beta-secretase 1) BACE1 and BACE2 inhibitor, with Ki values of 2.2 nM and 0.38 nM, respectively. |
| LX2343
LX2343 is a BACE1 enzyme inhibitor with IC50 value of 11.43±0.36 μM, and it is a neuroprotective agent. |
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