PF-06751979 is a potent, brain penetrant, β-site amyloid precursor protein cleaving enzyme 1 ( BACE1 ) inhibitor with an IC 50 of 7.3 nM in BACE1 binding assay. In Vitro PF-06751979 shows improved selectivity over BACE2 (IC 50 =194 nM) in binding (27-fold) relative to the literature examples and across multiple chemical series in BACE1 program. PF-06751979 also inhibits BACE1 and BACE2 in a fluorescent polarization (FP) assay with IC 50 s of 26.9 nM and 238 nM, respectively. PF-06751979 has excellent potency at BACE1 in binding or FP assay formats along with cellular activity looking at production of sAPPβ in H4 cells with an IC 50 of 5 nM. MCE has not independently confirmed the accuracy of these methods. They are for reference only. In Vivo PF-06751979 displays excellent brain penetration, potent in vivo efficacy, and broad selectivity over related aspartyl proteases including BACE2. Acute administration of PF-06751979 yields a robust dose-responsive and time-dependent reduction of cerebral spinal fluid (CSF) Aβx-40 with peak inhibition at 3 h of >77%. To determine if the reduction in brain and CSF Aβ is maintained during sustained exposure to PF-06751979, a 5 day subchronic study is executed, dosing once daily by subcutaneous (SC) administration (10 or 50 mg/kg/day). Brain and CSF samples are collected on day 5, following the last dose. PF-06751979 produces a dose-responsive and time-dependent inhibition of Aβ42 in mouse brain. At the 50 mg/kg/day dose, maximal brain lowering is 63% at 7 to 9 h. Administration of PF-06751979 (10 or 50 mg/kg/day for 5 days) produces a dose-responsive and time-dependent inhibition of Aβx-40 in mouse CSF resulting in 77% inhibition of CSF at 3 h post-final 50 mg/kg dose . MCE has not independently confirmed the accuracy of these methods. They are for reference only. Form:Solid IC50& Target:IC50: 7.3 nM (BACE1), 194 nM (BACE2)
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PF-06751979
CAS number：1818339-66-0 molecular formula：C18H19F2N5O3S2
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| Chinese alias | - | ||
| English alias | PF-06751979 | DB15105 | US9315520, Example 1 | 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 | AKOS040734426 | N-(2-((4aR,6S,8aR)-2-Amino-6-methyl-4a,5,6,8-tetrahyd | ||
| CAS number | 1818339-66-0 | molecular formula | C18H19F2N5O3S2 |
| molecular weight | 455.50 g/mol | Exact mass | ≥99% |
| PSA | 165.000 Ų | logp | 2.400 |
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