PF-06751979

Research use only, not for human use.

PF-06751979 is a potent, selective, brain penetrant BACE1 inhibitor with binding IC50 of 7.3, 27-fold selectivity over BACE2.

PF-06751979 is a potent, selective, brain penetrant BACE1 inhibitor with binding IC50 of 7.3, 27-fold selectivity over BACE2; shows BACE1 inhibition and sAPPβ production in whole-cell assay with IC50 of 5.1 and 5 nM; displays excellent brain penetration, potent in vivo efficacy, and broad selectivity over related aspartyl proteases including BACE2; demonstrates potent and dose-dependent Aβ lowering in human CSF with lacking hypopigmentation compared with AZD3239.Alzheimer Disease Phase 1 Clinical.

PF-06751979 shows improved selectivity over BACE2 (IC50=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 IC50s 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 IC50 of 5 nM.

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.

PF06751979

Metabolic Enzyme/Protease

BACE

BACE

Neurological Disease

Alzheimer Disease

1818339-66-0

455.499

C18H19F2N5O3S2

>98% (HPLC)

DMSO : 150 mg/mL 329.31 mM; Ethanol : 50 mg/mL 109.77 mM

CC1CC2CSC(=NC2(CO1)C3=NC(=CS3)NC(=O)C4=NC=C(C=C4)OC(F)F)N

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

(-20℃)

With Ice Pack

≥ 2 years