Design and Synthesis of Clinical Candidate PF-06751979: A Potent, Brain Penetrant, β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitor Lacking Hypopigmentation.

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.

• Authors: Brian T O'Neill, Elizabeth M Beck, Christopher R Butler, Charles E Nolan, Cathleen Gonzales, Lei Zhang, Shawn D Doran, Kimberly Lapham, Leanne M Buzon, Jason K Dutra, Gabriela Barreiro, Xinjun Hou, Luis A Martinez-Alsina, Bruce N Rogers, Anabella Villalobos, John C Murray, Kevin Ogilvie, Erik A LaChapelle, Cheng Chang, Lorraine F Lanyon, Claire M Steppan, Ashley Robshaw, Katherine Hales, Germaine G Boucher, Karamjeet Pandher, Christopher Houle, Claude W Ambroise, David Karanian, David Riddell, Kelly R Bales, Michael A Brodney
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 61 Issue 10 Pg. 4476-4504 (05 24 2018) ISSN: 1520-4804 [Electronic] United States
• PMID: 29613789 (Publication Type: Journal Article)

Chemical References

• Amyloid beta-Protein Precursor
• PF-06751979
• Protease Inhibitors
• Pyrans
• Thiazines
• Thiazoles
• Amyloid Precursor Protein Secretases
• Aspartic Acid Endopeptidases
• BACE1 protein, human
• Bace1 protein, mouse

Topics

• Amyloid Precursor Protein Secretases (antagonists & inhibitors)
• Amyloid beta-Protein Precursor (metabolism)
• Animals
• Aspartic Acid Endopeptidases (antagonists & inhibitors)
• Brain (drug effects, metabolism)
• Cells, Cultured
• Dogs
• Drug Design
• Humans
• Hypopigmentation (chemically induced)
• Male
• Melanocytes (drug effects)
• Mice
• Mice, Inbred C57BL
• Models, Molecular
• Molecular Structure
• Protease Inhibitors (administration & dosage, adverse effects, chemistry)
• Protein Conformation
• Pyrans (administration & dosage, adverse effects, chemistry)
• Skin Pigmentation (drug effects)
• Thiazines (administration & dosage, adverse effects, chemistry)
• Thiazoles (administration & dosage, adverse effects, chemistry)