Back to Search
Start Over
Design and Synthesis of Clinical Candidate PF-06751979: A Potent, Brain Penetrant, β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitor Lacking Hypopigmentation.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2018 May 24; Vol. 61 (10), pp. 4476-4504. Date of Electronic Publication: 2018 Apr 17. - Publication Year :
- 2018
-
Abstract
- 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.
- Subjects :
- Amyloid beta-Protein Precursor metabolism
Animals
Brain drug effects
Cells, Cultured
Dogs
Humans
Male
Melanocytes drug effects
Mice
Mice, Inbred C57BL
Models, Molecular
Molecular Structure
Protein Conformation
Amyloid Precursor Protein Secretases antagonists & inhibitors
Aspartic Acid Endopeptidases antagonists & inhibitors
Brain metabolism
Drug Design
Hypopigmentation chemically induced
Protease Inhibitors administration & dosage
Protease Inhibitors adverse effects
Protease Inhibitors chemistry
Pyrans administration & dosage
Pyrans adverse effects
Pyrans chemistry
Skin Pigmentation drug effects
Thiazines administration & dosage
Thiazines adverse effects
Thiazines chemistry
Thiazoles administration & dosage
Thiazoles adverse effects
Thiazoles chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 61
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 29613789
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.8b00246