| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| Other Sizes |
Purity: ≥98%
| Targets |
PF-06751979 targets BACE1 (β-site amyloid precursor protein cleaving enzyme 1), a transmembrane aspartyl protease that initiates the production of amyloid-β (Aβ) peptides from the amyloid precursor protein (APP). BACE1 is the rate-limiting enzyme in the amyloidogenic pathway and is a well-validated therapeutic target for Alzheimer's disease. PF-06751979 is a potent, brain-penetrant BACE1 inhibitor with an IC50 of 7.3 nM in BACE1 binding assays. The compound shows selectivity for BACE1 over BACE2 (IC50 = 273 nM). PF-06751979 lacks hypopigmentation, a side effect associated with some BACE1 inhibitors.
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| ln Vitro |
PF-06751979 demonstrated a 27-fold greater binding selectivity (IC50= 194 nM) than BACE2 in comparison to literature examples and several chemical series in the BACE1 program. Using IC50 values of 238 nM and 26.9 nM, respectively, PF-06751979 also inhibits BACE1 and BACE2 in fluorescence polarization (FP) tests. PF-06751979 exhibits remarkable efficacy against BACE1 in binding or FP test formats. Additionally, it has been reported to stimulate sAPPβ synthesis in H4 cells, with an IC50 of 5 nM [1].
PF-06751979 demonstrates potent in vitro activity as a BACE1 inhibitor. The compound has an IC50 of 7.3 nM in BACE1 binding assays. PF-06751979 shows an IC50 of 273 nM for BACE2, indicating approximately 37-fold selectivity for BACE1 over BACE2. The compound is brain-penetrant, supporting its utility for studying central nervous system targets. PF-06751979 lacks hypopigmentation, which is a potential advantage over some other BACE1 inhibitors. The compound's potent and selective BACE1 inhibition makes it a valuable tool for studying the role of BACE1 in amyloid-β production and Alzheimer's disease pathogenesis. |
| ln Vivo |
Strong in vivo efficacy, good brain penetration, and broad selectivity against related aspartyl proteases, such as BACE2, are all displayed by PF-06751979. When PF-06751979 was administered acutely, there was a significant, time- and dose-dependent decrease in CSF Aβx-40, with a peak inhibition of more than 77% at three hours. In order to ascertain whether persistent exposure to PF-06751979 results in decreases in brain and CSF Aβ, a 5-day subchronic trial was carried out using subcutaneous (SC) dosing once daily (10 or 50 mg/kg/day). Samples of the brain and cerebrospinal fluid were taken five days following the previous dose. PF-06751979 inhibits Aβ42 in the mouse brain in a time- and dose-dependent manner. The greatest reduction in brain size at 7 to 9 hours was 63% at 50 mg/kg/day. Aβx-40 in mouse CSF was dose-responsively and time-dependently inhibited after PF-06751979 (10 or 50 mg/kg/day) was administered for five days. The final 50 mg CSF inhibition occurred three hours after the 77%/kg dose[1].
PF-06751979 has been evaluated in vivo for its effects on amyloid-β production. The compound is brain-penetrant, allowing it to access its target in the central nervous system. PF-06751979 lacks hypopigmentation, a side effect associated with some BACE1 inhibitors that is thought to be due to inhibition of BACE2. The compound's brain penetration and selectivity for BACE1 over BACE2 support its utility for studying BACE1 inhibition as a therapeutic strategy for Alzheimer's disease. Detailed in vivo efficacy data, including effects on Aβ levels in brain and cerebrospinal fluid, are available in the primary literature. |
| Enzyme Assay |
The in vitro enzyme inhibition assay for PF-06751979 measures the inhibition of BACE1 enzymatic activity. Recombinant human BACE1 enzyme is incubated with varying concentrations of PF-06751979 (typically ranging from picomolar to micromolar) in the presence of a fluorescent or peptide substrate that mimics the APP cleavage site. The enzymatic reaction is monitored by measuring the cleavage of the substrate, which releases a fluorescent or chromogenic product. IC50 values are determined by fitting dose-response curves to the inhibition data (7.3 nM for BACE1). The compound is dissolved in DMSO and diluted in assay buffer. Selectivity is assessed by testing the compound against BACE2 (IC50 = 273 nM). Appropriate positive controls and negative controls are included in each assay run.
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| Cell Assay |
The in vitro cellular assay for PF-06751979 is performed using cells that express APP and BACE1, such as neuronal cell lines or HEK293 cells transfected with APP. Cells are cultured in appropriate medium and treated with varying concentrations of PF-06751979 or vehicle control (DMSO) for specified time points. Aβ levels in the culture medium are measured by ELISA or by using a reporter system. The inhibition of Aβ production is quantified, and IC50 values are determined. The compound's effects on APP processing and other cellular pathways can also be assessed by Western blotting.
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| Animal Protocol |
In vivo animal experiments with PF-06751979 are conducted using rodent models of Alzheimer's disease or wild-type mice. PF-06751979 is administered orally or intraperitoneally at various doses. Brain penetration is confirmed by measuring compound concentrations in brain and plasma. Aβ levels in brain homogenates and cerebrospinal fluid are measured by ELISA. The compound's effects on Aβ reduction are quantified and compared to vehicle-treated controls. The compound's effects on pigmentation are assessed to confirm the lack of hypopigmentation. Detailed experimental protocols are described in the primary literature.
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| ADME/Pharmacokinetics |
Detailed pharmacokinetic (PK) parameters for PF-06751979 are partially documented. The compound is brain-penetrant. PF-06751979 has a molecular weight of 455.5 and a chemical formula of C18H19F2N5O3S2. The compound is soluble in DMSO at ≥60 mg/mL. The compound should be stored as a powder at -20°C for 3 years or at 4°C for 2 years. Detailed PK parameters including half-life, clearance, volume of distribution, and maximum concentration (Cmax) are available in the primary literature and should be consulted for specific experimental planning.
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| Toxicity/Toxicokinetics |
Comprehensive toxicological data for PF-06751979 are not extensively documented in publicly available sources. The compound lacks hypopigmentation, suggesting a reduced risk of this particular side effect compared to some other BACE1 inhibitors. As a research-grade compound, PF-06751979 is intended for laboratory research purposes only and is not approved for human therapeutic use. Standard laboratory safety practices should be followed when handling this compound, including the use of appropriate personal protective equipment and working in a well-ventilated area. The compound should be stored according to the manufacturer's recommendations to maintain stability and prevent degradation.
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| References | |
| Additional Infomation |
PF-06751979 is being studied in the clinical trial NCT03126721 (which aims to evaluate the effects of multiple doses of PF-06751979 on the pharmacokinetics of midazolam in healthy adults).
PF-06751979 is a research compound developed for studying the role of BACE1 in Alzheimer's disease and for evaluating BACE1 inhibition as a therapeutic strategy. The compound is a potent, brain-penetrant BACE1 inhibitor with an IC50 of 7.3 nM and selectivity over BACE2 (IC50 = 273 nM). PF-06751979 lacks hypopigmentation, a side effect associated with some BACE1 inhibitors. PF-06751979 is not currently in clinical trials nor approved for therapeutic use; it remains an investigational tool compound for preclinical Alzheimer's disease research. PF-06751979 is available from various chemical suppliers for research purposes. |
| Molecular Formula |
C18H19F2N5O3S2
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|---|---|
| Molecular Weight |
455.501967668533
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| Exact Mass |
455.089
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| CAS # |
1818339-66-0
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| Related CAS # |
1818339-66-0;1818339-67-1 (HCl);
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| PubChem CID |
118435360
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| Appearance |
White to off-white solid powder
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| LogP |
2.4
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
30
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| Complexity |
676
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| Defined Atom Stereocenter Count |
3
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| SMILES |
S1C(N)=N[C@@]2(C3=NC(=CS3)NC(C3C=CC(=CN=3)OC(F)F)=O)CO[C@@H](C)C[C@H]2C1
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| InChi Key |
ZLZUHACSRMOLLV-RAALSFIWSA-N
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| InChi Code |
InChI=1S/C18H19F2N5O3S2/c1-9-4-10-6-30-17(21)25-18(10,8-27-9)15-24-13(7-29-15)23-14(26)12-3-2-11(5-22-12)28-16(19)20/h2-3,5,7,9-10,16H,4,6,8H2,1H3,(H2,21,25)(H,23,26)/t9-,10-,18-/m0/s1
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| Chemical Name |
N-(2-((4aR,6S,8aR)-2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl)thiazol-4-yl)-5-(difluoromethoxy)picolinamide
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| Synonyms |
PF06751979; PF 06751979; PF-06751979
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| HS Tariff Code |
2934.99.9001
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| 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)
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| Solubility (In Vitro) |
DMSO : ~150 mg/mL (~329.31 mM)
Ethanol : ~50 mg/mL (~109.77 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.75 mg/mL (6.04 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (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 27.5 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: ≥ 2.75 mg/mL (6.04 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 27.5 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 | 2.1954 mL | 10.9769 mL | 21.9539 mL | |
| 5 mM | 0.4391 mL | 2.1954 mL | 4.3908 mL | |
| 10 mM | 0.2195 mL | 1.0977 mL | 2.1954 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.
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