292632-98-5

Usage

Uses

Used in Pharmaceutical Research:
L-685,458 is used as a research tool for studying the role of γ-secretase in the development of Alzheimer's disease. By inhibiting this enzyme, it helps researchers understand the underlying mechanisms and potential therapeutic targets for treating the disease.
Used in Alzheimer's Disease Treatment:
L-685,458 is used as a potential therapeutic agent for Alzheimer's disease, as it inhibits the production of amyloid β-peptide, which is a key factor in the development of the disease.
Used in Notch Signaling Attenuation:
L-685,458 is used as a compound to attenuate Notch signaling in ovary culture, which can be useful for studying the role of Notch signaling in various biological processes and potential therapeutic applications.
Used in Analyzing γ-Secretase Specificity:
L-685,458 is used as a tool to analyze the specificity of γ-secretase activity in brain tissue samples, which can help researchers understand the enzyme's role in different brain functions and its potential as a therapeutic target for various neurological disorders.

Biological Activity

Potent and selective γ -secretase inhibitor (IC 50 = 17 nM) that displays > 50-fold selectivity over a range of aspartyl, serine and cysteine proteases. Exhibits equal potency for inhibition of A β 40 and A β 42 peptides (IC 50 values are 48 and 67 nM respectively in human neuroblastoma cells). Also regulates CXCR4 and VEGFR2 expression through inhibition of Notch signaling in vitro .

Biochem/physiol Actions

L-685,458 mimics the transition state in aspartyl protease. It possesses an IC50 of 17nM with respect to inhibition of Aβ synthesis. It is known to block Notch (neurogenic locus notch homolog protein) signaling, which in turn reduces ERK (extracellular signal regulated kinase) phosphorylation by EGF (epidermal growth factor). L-685,458 targets the active site and substrate binding site of the enzyme.

Upstream product

• 126410-32-0 {(1S,2S,4R)-1-Benzyl-2-(tert-butyl-dimethyl-silanyloxy)-4-[(S)-1-((S)-1-carbamoyl-2-phenyl-ethylcarbamoyl)-3-methyl-butylcarbamoyl]-5-phenyl-pentyl}-carbamic acid tert-butyl ester 
• 292620-20-3 (1S,4R)-{1-benzyl-4-[1-(1S)-carbamoyl-(2-phenylethylcarbamoyl)-(1S)-3-methylbutylcarbamoyl]-2-oxo-5-phenylpentyl}carbamic acid tert-butyl ester 
• 13139-15-6 N-tert-butoxycarbonyl-L-leucine 
• 5241-58-7 L-Phenylalanine amide 
• 13734-34-4 N-tert-butoxycarbonyl-L-phenylalanine 
• 88463-18-7 (S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropionamide 
• 33900-15-1 (2S)-N-[(1S)-2-amino-1-benzyl-2-oxoethyl]-2-[(tert-butoxycarbonyl)amino]-4-methylpentanamide 
• 38678-60-3 leucylphenylalanylamide 
• 98818-41-8 (3R,5S)-3-benzyl-5-{(1S)-1-[(tert-butoxycarbonyl)amino]-2-phenylethyl}dihydrofuran-2-(3H)-one 
• 98818-45-2 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-phenylmethylhexanoic acid 
• 98818-51-0 N-(1,1-dimethylethoxycarbonyl)-5(S)-amino-4(S)-(t-butyldimethylsilyloxy)-6-phenyl-2(R)-(phenylmethyl)hexanoic acid 
• 63-91-2 L-phenylalanine 
• 72155-45-4 Boc-L-phenylalaninal 
• 98818-48-5 C₃₆H₅₉NO₅Si₂ 

Downstream Products

• 98818-74-7 L-364,505 

Relevant academic research and scientific papers

Allyltrichlorostannane additions to α-amino aldehydes: Application to the total synthesis of the aspartyl protease inhibitors L-682,679, L-684,414, L-685,434, and L-685,458

The hydroxyethylene dipeptide isosteres L-682,679, L-684,414, L-685,434, and L-685,458 were synthesized in a few steps by a sequence involving an allyltrichlorostannane coupling with an α-amino aldehyde, followed by hydroboration of the corresponding 1,2-

Gamma secretase inhibitors

Gamma-secretase inhibitors, useful in the treatment or prevention of Alzheimer's disease, are disclosed. The preferred compounds have, as the central portion of the molecule, the structure (a) and are diastereoisomers of known protease inhibitors.

Short total synthesis of aspartyl protease inhibitors L-685,434, L-682,679 and L-685,458

Hydroxyethylene dipeptide isosteres L-685,434, L-682,679 and L-685,458 were synthesized in a few steps by a sequence involving an allyltrichlorostannane coupling with an α-aminoaldehyde followed by hydroboration of the corresponding 1,2-syn and 1,2-anti a

A stereocontrolled synthesis of 2R-benzyl-5S-tert-butoxycarbonylamino-4R-(tert-butyldimethylsilanyloxy)-6- phenyl-hexanoic acid (Phe-Phe hydroxyethylene dipeptide isostere)

2R-Benzyl-5S-tert-butoxycarbonylamino-4R-(tert-butyldimethylsilanyloxy)-6- phenyl-hexanoic acid, a hydroxyethylene dipeptide isostere corresponding to Phe-Phe, has been synthesized in a practical, stereocontrolled fashion from (L)-phenylalanine.

HIV-1 protease inhibitors based on hydroxyethylene dipeptide isosteres: An investigation into the role of the P1' side chain on structure-activity

A systematic investigation was undertaken to determine the role of the P1' sidechain in a series of hydroxyethylene isostere based inhibitors of HIV-1 protease. Substitution and homologation of the benzyl P1' side chain of the Phe-Phe isostere based pseudo peptides 1 (L-682,679) and 2 (L-685,434) with various heteroalkyl groups leads to a series of extremely potent inhibitors of the enzyme. Several examples of the most potent inhibitors were very effective in an ex vivo cell based viral spread assay using human H9 T- lymphocytes and the IIIb isolate of HIV-1. Compound 19 is 120 times more potent than 1 and 16 times more potent than 2 in inhibiting the spread of infection in this assay.

Design and synthesis of HIV protease inhibitors. Variations of the carboxy terminus of the HIV protease inhibitor L-682,679

A series of tetrapeptide analogues of 1 (L-682,679), in which the carboxy terminus has been shortened and modified, was prepared and their inhibitory activity measured against the HIV protease in a peptide cleavage assay. Selected examples were tested as inhibitors of virus spread in cell culture. Compound 12 was a 10-fold more potent enzyme inhibitor than 1 in vitro and 30-fold more potent in inhibiting the viral spread in cells.