65169-63-3Relevant articles and documents
Design and Synthesis of Clinical Candidate PF-06751979: A Potent, Brain Penetrant, β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitor Lacking Hypopigmentation
O'Neill, Brian T.,Beck, Elizabeth M.,Butler, Christopher R.,Nolan, Charles E.,Gonzales, Cathleen,Zhang, Lei,Doran, Shawn D.,Lapham, Kimberly,Buzon, Leanne M.,Dutra, Jason K.,Barreiro, Gabriela,Hou, Xinjun,Martinez-Alsina, Luis A.,Rogers, Bruce N.,Villalobos, Anabella,Murray, John C.,Ogilvie, Kevin,Lachapelle, Erik A.,Chang, Cheng,Lanyon, Lorraine F.,Steppan, Claire M.,Robshaw, Ashley,Hales, Katherine,Boucher, Germaine G.,Pandher, Karamjeet,Houle, Christopher,Ambroise, Claude W.,Karanian, David,Riddell, David,Bales, Kelly R.,Brodney, Michael A.
, p. 4476 - 4504 (2018/05/31)
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. Herein, we describe the identification of clinical candidate PF-06751979 (64), which 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.
TETRAHYDROPYRANO[3,4-D][1,3]OXAZIN DERIVATIVES AND THEIR USE AS BACE INHIBITORS
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Page/Page column 72; 73, (2017/04/11)
The present invention is directed to compounds, tautomers and pharmaceutically acceptable salts of the compounds which are disclosed, wherein the compounds have the structure of Formula (I), wherein the variables R1, R2, R3, R4 and X are as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.
2-AMINO-6-METHYL-4,4a,5,6-TETRAHYDROPYRANO[3,4-d][1,3]THIAZIN-8a(8H)-YL-1,3-THIAZOL-4-YL AMIDES
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Page/Page column 89; 90, (2015/11/17)
The present invention is directed to compounds, tautomers and pharmaceutically acceptable salts of the compounds which are disclosed, wherein the compounds have the structure of Formula (I), and the variable R1 is as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.