| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
|
||
| 5mg |
|
||
| 10mg |
|
||
| 25mg |
|
||
| 100mg | |||
| Other Sizes |
| Targets |
NGP-555 targets γ-secretase, a multi-subunit intramembrane protease complex that cleaves APP to generate Aβ peptides. Unlike full γ-secretase inhibitors, NGP-555 acts as a modulator that shifts the cleavage pattern away from the toxic Aβ42 species toward shorter, less amyloidogenic Aβ isoforms. It inhibits APP intracellular signaling domain (AICD) cleavage to Aβ with IC₅₀ values of 531 nM (Aβ40) and 131 nM (Aβ42). This modulation preserves Notch signaling while reducing Aβ42 production.
|
|---|---|
| ln Vitro |
In cell culture, NGP555 efficiently lowers Aβ42 (9 nM) while raising shorter forms of Aβ [1].
In vitro, NGP-555 potently lowers Aβ42 in cell cultures at 9 nM while simultaneously increasing shorter forms of Aβ. This indicates a shift in γ-secretase cleavage specificity rather than complete enzyme inhibition. The compound's IC₅₀ values for Aβ40 and Aβ42 are 531 nM and 131 nM, respectively. It shows efficacy in various cell-based models of amyloid production. The compound does not completely block γ-secretase activity, thereby avoiding potential Notch-related toxicity. |
| ln Vivo |
Panel B shows the considerable reduction of Aβ42 in cerebrospinal fluid (CSF) after 8 to 10 hours of dosage with NGP555. Panel C shows a significant decrease in Aβ levels in CSF at 3.75 mg/kg and higher when NGP555 was used. It was demonstrated that at NGP555 doses of 15 mg/kg and above, Aβ38 levels rose. NGP555 successfully raises the CSF Aβ38/42 ratio to 1.87 mg/kg and above when the decrease in Aβ42 is paired with the increase in Aβ38 (Figure D). NGP555-treated Tg mice demonstrated considerable protection against performance decline, lowering the decline by more than 65% (P<0.005) when compared to non-Tg vehicle-treated mice. NGP555 also shows good brain penetration and oral bioavailability in mice, with a brain:plasma ratio of roughly 0.93 [1].
In vivo, NGP-555 significantly reduces Aβ42 in cerebrospinal fluid (CSF) at 8-10 hours post-administration at 3.75 mg/kg. Transgenic mice treated with NGP-555 show significant cognitive protection, with performance decline reduced by >65% compared to control transgenic mice (P<0.005). The compound demonstrates good oral bioavailability and brain penetration, with a brain:plasma ratio of approximately 0.93 in mice. NGP-555 shows markedly higher exposure levels (~20-fold) versus efficacious levels before liver enzyme increases in rat studies. |
| Enzyme Assay |
In vitro γ-secretase activity assays typically use cell membrane fractions or purified γ-secretase complex incubated with recombinant APP substrate or fluorogenic substrates. NGP-555 is dissolved in DMSO and diluted in assay buffer. Reactions are initiated by adding substrate and incubated at 37°C for 2-4 hours. Aβ40 and Aβ42 levels are quantified by ELISA or immunoassay. IC₅₀ values are calculated from dose-response curves. Controls include DMSO vehicle and a known γ-secretase inhibitor (e.g., DAPT) for comparison. Notch cleavage may be assessed to confirm modulator vs. inhibitor profile.
|
| Cell Assay |
For cell-based assays, cells expressing APP (e.g., CHO-APP or SH-SY5Y-APP) are cultured in appropriate medium with 10% FBS. Cells are seeded in 96-well plates and treated with NGP-555 at various concentrations (0.1 nM-10 μM) for 24-48 hours. Conditioned media are collected for Aβ40 and Aβ42 quantification by ELISA or MSD assays. Cell viability is assessed by MTT or CellTiter-Glo. Intracellular APP processing may be analyzed by Western blotting. All treatments include vehicle controls and are performed in triplicate.
|
| Animal Protocol |
In vivo, NGP-555 is typically administered orally or via intraperitoneal injection to transgenic mouse models of Alzheimer's disease (e.g., APP/PS1 or Tg2576 mice). Dosing regimens may involve daily administration at 0.5-10 mg/kg for 2-6 months. CSF is collected from cisterna magna for Aβ42 measurement at specified time points post-dose. Cognitive function is assessed using Morris water maze, Y-maze, or novel object recognition tests. Brain tissues are collected for Aβ plaque quantification by immunohistochemistry and biochemical analysis. Plasma and brain drug concentrations are measured by LC-MS/MS.
|
| ADME/Pharmacokinetics |
NGP-555 demonstrates good oral bioavailability and blood-brain barrier penetration in preclinical studies. In mice, the brain:plasma ratio is approximately 0.93, indicating efficient central nervous system distribution. Exposure levels are markedly higher (~20-fold) than efficacious levels before liver enzyme increases in rat studies. In beagle dog toxicity studies, no increase in liver enzymes was observed up to and beyond the no-observable adverse effect level (NOAEL). The compound is metabolized by hepatic enzymes. Further detailed PK parameters are available in preclinical reports.
|
| Toxicity/Toxicokinetics |
In rat studies, NGP-555 shows markedly higher exposure levels (~20-fold) versus efficacious levels before liver enzymes are increased. In beagle dog toxicity studies, no increase in liver enzymes was observed up to and beyond the NOAEL. This suggests a favorable safety margin for the compound. Standard toxicology studies (acute, subchronic, genotoxicity) have been conducted as part of preclinical development. The compound appears well-tolerated at therapeutic doses. Long-term safety data are available from preclinical study reports. The compound is for research use only.
|
| References | |
| Additional Infomation |
NGP-555 is a γ-secretase modulator being investigated for Alzheimer's disease. Unlike full γ-secretase inhibitors, it lowers Aβ42 while preserving Notch signaling by increasing shorter Aβ forms. The compound has advanced to preclinical development stages. It is not yet approved for clinical use. Its mechanism offers potential for disease-modifying therapy in Alzheimer's disease. The compound is commercially available from various chemical suppliers for research purposes only.
|
| Molecular Formula |
C23H23FN4S
|
|---|---|
| Molecular Weight |
406.5234
|
| Exact Mass |
406.162
|
| CAS # |
1304630-27-0
|
| PubChem CID |
46853593
|
| Appearance |
White to off-white solid powder
|
| Density |
1.2±0.1 g/cm3
|
| Boiling Point |
574.9±60.0 °C at 760 mmHg
|
| Flash Point |
301.5±32.9 °C
|
| Vapour Pressure |
0.0±1.6 mmHg at 25°C
|
| Index of Refraction |
1.643
|
| LogP |
6.24
|
| Hydrogen Bond Donor Count |
1
|
| Hydrogen Bond Acceptor Count |
5
|
| Rotatable Bond Count |
5
|
| Heavy Atom Count |
29
|
| Complexity |
537
|
| Defined Atom Stereocenter Count |
0
|
| InChi Key |
WDEKUGNKKOGFOA-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C23H23FN4S/c1-5-17-10-20(15(3)8-14(17)2)26-23-27-21(12-29-23)18-6-7-22(19(24)9-18)28-11-16(4)25-13-28/h6-13H,5H2,1-4H3,(H,26,27)
|
| Chemical Name |
N-(5-ethyl-2,4-dimethylphenyl)-4-[3-fluoro-4-(4-methylimidazol-1-yl)phenyl]-1,3-thiazol-2-amine
|
| Synonyms |
NGP555; NGP 555; NGP-555
|
| HS Tariff Code |
2934.99.9001
|
| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
DMSO : ~25 mg/mL (~61.50 mM)
|
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (6.15 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (6.15 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4599 mL | 12.2995 mL | 24.5990 mL | |
| 5 mM | 0.4920 mL | 2.4599 mL | 4.9198 mL | |
| 10 mM | 0.2460 mL | 1.2300 mL | 2.4599 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
