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In 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 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 |
|---|
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AZ-4217 is an inhibitor for β-site amyloid precursor protein cleavage enzyme 1 (BACE1), with IC50 of 160 pM in human SH-SY5Y cells. |
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| Glabrolide
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| Kushenol C
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| Deoxyneocryptotanshinone
Deoxyneocryptotanshinone is a high affinity BACE1 (Beta-secretase) inhibitor with an IC50 value of 11.53 μM. Deoxyneocryptotanshinone shows a promising dose-dependent inhibition of protein tyrosine phosphatase 1B (PTP1B) with an IC50 value of 133.5 μM. |
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