product name L-685458
Description: L-685,458 (also known as L685458) is a novel, specific, potent, selective inhibitor of A beta PP γ-secretase activity with Ki of 17 nM. It displays > 50-fold selectivity over a range of aspartyl, serine and cysteine proteases. L685458 also exhibits equal potency for inhibition of A β 40 and A β 42 peptides (IC50 values are 48 and 67 nM respectively in human neuroblastoma cells). Also regulates CXCR4 and VEGFR2 expression through inhibition of Notch signaling in vitro.
References: Biochemistry. 2000 Aug 1;39(30):8698-704; J Neurochem. 2001 Jan;76(1):173-81; J Pharmacol Exp Ther. 2003 Jun;305(3):864-71.
672.85
Formula
C39H52N4O6
CAS No.
292632-98-5
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 100 mg/mL (148.6 mM)
Water: <1 mg/mL
Ethanol: 6 mg/mL warmed (8.9 mM)
Solubility (In vivo)
Synonyms
other peoduct :References PubMed ID：:http://www.ncbi.nlm.nih.gov/pubmed/19422333
| In Vitro |
In vitro activity: L-685,458 inhibits Aβ(40) formation in both Neuro2A and CHO cell lines overexpressing human AβPP695, and in SHSY5Y cells overexpressing the construct spβA4CTF with IC50 of 402 nM, 113 nM, and 48 nM, respectively, with the potency for reduction of Aβ(42) being about 2-fold lower. In Tca8113 cells, L-685,458 inhibits cell growth by inducing G0–G1 cell cycle arrest and apoptosis. In a T-cell acute lymphoblastic leukemia cell line, pre-treatment with L-685,458 enhances the anti-proliferative effect of imatinib. L685,458 also significantly reduces HSV-1 replication in tissue culture by inhibiting signal peptide peptidase (SPP). Kinase Assay: Cell Assay: It is a pan-inhibitor of γ-secretase which decrease the products of Aβ(42) and Aβ(40) peptides. It displays a selectivity of 50-fold or greater inhibition than a range of aspartyl, serine, and cysteine protease in vitro membrane assay. L-685,458 reduced the product both total Aβand Aβ42 in human primary neuronal cells with IC50 value of 115 nM for Aβand Aβ42 for 200 nM[2]. L-685,458 also inhibitedγ-secretase activity by characterizing the production of total secreted Aβby ELISA with IC50 value of about 5 nM in HEK 293 cells overexpressing human APP751. |
|---|---|
| In Vivo | L-685,458 reduced the cortical total Aβwith a 50% reduction occurring at 100 mg/kg in a dose-dependent manner in PDAPP, and similar reductions in cortical Aβ42 were observed. L-685,458 decreased brain levels of Aβwhen given orally to Tg2576 mice that are transgenic for human APPV717F mutation. L-685,458 also inhibit the Notch signaling, then affects embryonic development in zebrafish embryos. |
| Animal model | Mouse model |
| Formulation & Dosage | 10 mg/kg; p.o. |
| References | Biochemistry. 2000 Aug 1;39(30):8698-704; J Neurochem. 2001 Jan;76(1):173-81; J Pharmacol Exp Ther. 2003 Jun;305(3):864-71. |
