PF-06751979 (PF06751979) is a novel, highly potent, brain penetrant, and selective inhibitor of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) with the potential to be used for the treatment of Alzheimer's disease. It inhibits BACE1 with an IC50 of 7.3 nM in BACE1 binding assay. PF-06751979 displays excellent brain penetration, potent in vivo efficacy, and broad selectivity over related aspartyl proteases including BACE2. Chronic dosing of 64 for up to 9 months in dog did not reveal any observation of hair coat color (pigmentation) changes and suggests a key differentiator over current BACE1 inhibitors that are nonselective against BACE2 in later stage clinical development. A major challenge in the development of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors for the treatment of Alzheimer's disease is the alignment of potency, drug-like properties, and selectivity over related aspartyl proteases such as Cathepsin D (CatD) and BACE2. The potential liabilities of inhibiting BACE2 chronically have only recently begun to emerge as BACE2 impacts the processing of the premelanosome protein (PMEL17) and disrupts melanosome morphology resulting in a depigmentation phenotype.
Physicochemical Properties
| Molecular Formula | C18H19F2N5O3S2 |
| Molecular Weight | 455.501967668533 |
| Exact Mass | 455.089 |
| CAS # | 1818339-66-0 |
| Related CAS # | 1818339-66-0;1818339-67-1 (HCl); |
| PubChem CID | 118435360 |
| Appearance | White to off-white solid powder |
| LogP | 2.4 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 10 |
| Rotatable Bond Count | 5 |
| Heavy Atom Count | 30 |
| Complexity | 676 |
| Defined Atom Stereocenter Count | 3 |
| 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 |
| InChi Key | ZLZUHACSRMOLLV-RAALSFIWSA-N |
| 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 |
| 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 |
| Synonyms | PF06751979; PF 06751979; PF-06751979 |
| 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) |
Biological Activity
| 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]. |
| 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]. |
| References |
[1]. Design and Synthesis of Clinical Candidate PF-06751979: A Potent, Brain Penetrant, β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitor Lacking Hypopigmentation. J Med Chem. 2018 May 24;61(10):4476-4504. |
| Additional Infomation | PF-06751979 is under investigation in clinical trial NCT03126721 (The Study is to Evaluate the Effect of Multiple Doses PF-06751979 on the Pharmacokinetics of Midazolam in Healthy Adults). |
Solubility Data
| Solubility (In Vitro) |
DMSO : ~150 mg/mL (~329.31 mM) Ethanol : ~50 mg/mL (~109.77 mM) |
| 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 |