208255-80-5

Basic information

• Product Name: DAPT
• Synonyms: LY-374973, N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester;γ-Secretase Inhibitor IX;N-[(3,5-Difluorophenyl)acetyl]-L-alanyl-2-phenyl]glycine-1,1-dimethylethylester;SC-201315;(2S)-N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-2-phenylglycine tert-butyl ester;DAPT (enzyme inhibitor);GSI-IX;DAPT (GSI-IX)
• CAS NO: 208255-80-5
• Molecular Formula: C₂₃H₂₆F₂N₂O₄
• Molecular Weight: 432.464
• Product Categories: Angiogenesis and Metastasis;Protease inhibitor;Inhibitor;GSI-IX;Inhibitors
• Mol File: 208255-80-5.mol
• Article Data: 3

Chemical Properties

• Boiling Point: 612.2 °C at 760 mmHg
• Flash Point: 324.1 °C
• Appearance: white/solid
• Density: 1.213
• Vapor Pressure: 6.31E-15mmHg at 25°C
• Refractive Index: 1.534
• Storage Temp.: 2-8°C
• Solubility: DMSO: ~18 mg/mL
• PKA: 12.82±0.46(Predicted)
• Sensitive: Light Sensitive
• Stability: Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20° for up to 3 months.
• CAS DataBase Reference: DAPT(CAS DataBase Reference)
• NIST Chemistry Reference: DAPT(208255-80-5)
• EPA Substance Registry System: DAPT(208255-80-5)

Safety Data

• Safety Statements: 24/25
• WGK Germany: 3
• Hazardous Substances Data: 208255-80-5(Hazardous Substances Data)

Usage

Description

DAPT, also known as GSI-IX, is a potent and specific γ-secretase inhibitor. It is an inhibitor that effectively reduces the production of amyloid-beta (Aβ) peptides, which are associated with Alzheimer's disease. DAPT exhibits cell permeability and has been shown to reduce Aβ levels in brain extract, cerebrospinal fluid, and plasma from mice and rats. Additionally, DAPT blocks Notch signaling, which plays a role in neuronal differentiation, autoimmune diseases, and cancer cell growth.

Uses

Used in Alzheimer's Disease Research:
DAPT is used as a research tool for studying the formation of β-amyloid and its role in Alzheimer's disease. By inhibiting γ-secretase, DAPT helps researchers understand the underlying mechanisms of Aβ production and its contribution to the pathology of the disease.
Used in Autoimmune and Lymphoproliferative Diseases:
DAPT is used as a therapeutic agent for studying and potentially treating autoimmune and lymphoproliferative diseases such as Autoimmune Lymphoproliferative Syndrome (ALPS) and lupus erythematosus. By blocking Notch signaling, DAPT may help modulate the immune response and alleviate disease symptoms.
Used in Cancer Research:
DAPT is used as an inhibitor of cancer cell growth, angiogenesis, and differentiation. Its ability to block Notch signaling makes it a valuable tool in studying the role of this pathway in cancer development and progression.
Used in Stem Cell Research:
DAPT is used as a compound to enhance induced pluripotent stem (iPS) cells without the need for oncogenes such as KLF4 and CMYC. This application may help researchers develop safer and more efficient methods for generating iPS cells for regenerative medicine and other therapeutic applications.

Biological Activity

Inhibitor of γ -secretase; causes a reduction in A β 40 and A β 42 levels in human primary neuronal cultures (IC 50 values are 115 and 200 nM for total A β and A β 42 respectively) and in brain extract, cerebrospinal fluid and plasma in vivo . Does not effect APP α and APP β levels. Blocks Notch signaling in hybrid human-mouse foetal thymus organ culture (FTOC). Activity causes neural cells to commit to neuronal differentiation.

Biochem/physiol Actions

DAPT is a γ-secretase inhibitor and indirectly an inhibitor of Notch, a γ-secretase substrate. Other γ-secretase substrates include LDL receptor-related protein, E-cadherin and ErbB-4. As an inhibitor of γ-secretase, DAPT may be useful in the study of β-amyloid (Aβ) formation. DAPT has been shown to inhibit Notch signaling in studies of autoimmune and lymphoproliferative diseases, such as ALPS and lupus erythematosus (SLE), as well as in cancer cell growth, angiogenesis, and differentiation of human induced pluripotent stem cells (hIPSC).

References

1) Dovey?et al. (2001),?Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain; J. Neurochem.,?76?173 2) Portelius?et al. (2009),?Effects of γ-secretase inhibition on the amyloid β isoform pattern in a mouse model of Alzheimer’s disease; Cell Signal.,?5?615 3) El Moueddon?et al. (2006),?Reduction of Aβ levels in the Sprague Dawley rat after oral administration of the functional γ-secretase inhibitor, DAPT: a novel non-transgenic model for Aβ production inhibitors; Curr. Pharma. Des.,?12?1671 4) De Smedt?et al. (2005), Different thresholds of notch signaling bias human precursor cells towards B-, NK-, monocytic/dendritic, or T-cell lineage in thymus microenvironment; Blood,?106?2236 5) Ichida?et al. (2014),?Notch inhibition allows oncogene-independent generation of iPS cells; Nature Chem. Biol.,?10?632

InChI:InChI=1/C23H26F2N2O4/c1-14(26-19(28)12-15-10-17(24)13-18(25)11-15)21(29)27-20(16-8-6-5-7-9-16)22(30)31-23(2,3)4/h5-11,13-14,20H,12H2,1-4H3,(H,26,28)(H,27,29)/t14-,20-/m0/s1

Upstream product

• 53934-78-4 (S)-2-amino-2-phenylacetic acid tert-butyl ester 
• 2935-35-5 (S)-2-phenylglycine 
• 860013-16-7 N-(N-carbobenzyloxy-L-alanyl)-(2S)-2-phenylglycine tert-butyl ester 
• 105184-38-1 3,5-difluorophenyl acetic acid 
• 327052-53-9 N-(L-alanyl)-(2S)-2-phenylglycine tert-butyl ester 

Downstream Products

• 263162-50-1 (2S)-({N-[(3,5-difluorophenyl)acetyl]-L-alanyl}amino)(phenyl)acetic acid 

Relevant articles and documents

Enhanced delivery of γ-secretase inhibitor DAPT into the brain via an ascorbic acid mediated strategy

Inhibition of γ-secretase, one of the enzymes responsible for the cleavage of the amyloid precursor protein (APP) to produce pathogenic Aβ peptides, is an attractive approach for the treatment of Alzheimer's disease. We designed a γ-secretase inhibitor bearing an ascorbic acid moiety which allows a specific delivery of the drug to the brain. Through, on the one hand, Aβ peptide production measurements by specific in vitro assays (γ-secretase cell free assay and cell based assay on HEK 293 APP transfected cells) and on the other hand through pharmacokinetic studies on animal models, the new inhibitor shows a good pharmacokinetic profile as well as a potent γ-secretase inhibitory activity In vitro. From the obtained results, it is expected that drug 2 will be mainly delivered to the CNS with a low diffusion in the peripheral tissues. Consequently the side effects of this γ-secretase inhibitor on the immune cells could be reduced. The Royal Society of Chemistry 2005.

Parallel synthesis of DAPT derivatives and their γ-secretase- inhibitory activity

Parallel synthesis of the C-terminal-modified DAPT (1) derivatives was accomplished utilizing our novel resin 7. Condensation reaction of the N-acylamino acid 10 with the amines 11a-o proceeded smoothly to give the corresponding amides 6a-o without any epimerization. Among the analogues, the benzophenonemethyl amide derivative 6o showed 30 times more potent activity than the original DAPT (1).