Uses
δ-Secretase inhibitor 11 (compound 11) is an orally active, potent, BBB-penetrated, non-toxic, selective and specific δ-secretase inhibitor, with an IC50 of 0.7 μM. δ-Secretase inhibitor 11 interacts with both the active site and allosteric site of δ-secretase. δ-Secretase inhibitor 11 attenuates tau and APP (amyloid precursor protein) cleavage. δ-Secretase inhibitor 11 ameliorates synaptic dysfunction and cognitive impairments in tau P301S and 5XFAD transgenic mouse models. δ-Secretase inhibitor 11 can be used for Alzheimer's disease research[1].
Biological Activity
Compound 11 (CP11) is an orally active and brain-penetrant delta-secretase (δ-secretase; AEP) inhibitor th at selectively blocks AEP (IC50 = 710 nM) but not other related cysteine proteases (Caspase-3/-8 IC50 = 31.86/86.71 μM, Cathepsin-S/-L IC50 >200 μM) via a dual active site-directed and allosteric mode of inhibition. CP11 inhibits Pala cellular AEP activity in cultures (IC50 = 800 nM) and improves cognitive functions in murine models of Alzheimerμs disease (AD) in vivo (10 mg/kg tau P301S or 5xFAD mice via daily p.o.) by reducing tau and APP cleavage, ameliorating synapse loss and augmenting long-term potentiation.
in vivo
δ-Secretase inhibitor 11 (compound 11) (10 mg/kg, Orally, once daily for 3 months) attenuates neuronal injury induced by OGD (oxygen-glucose deprivation), and specifically exerts neuroprotective actions[1].
δ-Secretase inhibitor 11 (0-10 mg/kg, Orally, once daily for 1.5 and 3 months) inhibits δ-secretase activity, attenuates Aβ deposition and cognitive deficits in 5XFAD mouse model[1].
| Animal Model: | Tau P301S transgenic mice (n=4 mice per group)[1] |
| Dosage: | 10 mg/kg |
| Administration: | Orally, once daily for 3 months |
| Result: | Significantly inhibited the activity of δ-secretase in both wild-type and tau P301S mice brain, increased PP2A activity, and attenuated the truncation and phosphorylation of tau in tau P301S mice. Ameliorated synaptic loss and restored synaptic dysfunction in tau P301S mice. |
| Animal Model: | 5XFAD mice[1] |
| Dosage: | 2, 5 or 10mgkg |
| Administration: | Orally, once daily for 1.5 and 3 months |
| Result: | Attenuated the β-secretase-mediated processing of APP, significantly decreased the concentrations of Aβ 1-40 and Aβ 1-42 in the brain lysates, and attenuated Aβ deposition in a time- and dose-dependent manner. |
IC 50
Caspase-3: 31.86 ± 1. μM (IC
50); Caspase-8: 86.71 ± 10 μM (IC
50)
References
[1] Zhang Z, et al. Inhibition of delta-secretase improves cognitive functions in mouse models of Alzheimer's disease. Nat Commun. 2017 Mar 27;8:14740. DOI:
10.1038/ncomms14740
![7-Morpholin-4-yl-benzo[1,2,5]oxadiazol-4-ylamine Structure](https://www.chemicalbook.com/StructureFile/ChemBookStructure6/GIF/CB3721759.gif)
