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

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

  • J Med Chem. 2018 May 24;61(10):4476-4504. doi: 10.1021/acs.jmedchem.8b00246.
Brian T O'Neill 1,  Elizabeth M Beck 2,  Christopher R Butler 2,  Charles E Nolan 3,  Cathleen Gonzales 3,  Lei Zhang 2,  Shawn D Doran 4,  Kimberly Lapham 4,  Leanne M Buzon 1,  Jason K Dutra 1,  Gabriela Barreiro 2,  Xinjun Hou 2,  Luis A Martinez-Alsina 1,  Bruce N Rogers 2,  Anabella Villalobos 2,  John C Murray 1,  Kevin Ogilvie 1,  Erik A LaChapelle 1,  Cheng Chang 4,  Lorraine F Lanyon 5,  Claire M Steppan 5,  Ashley Robshaw 3,  Katherine Hales 3,  Germaine G Boucher 6,  Karamjeet Pandher 6,  Christopher Houle 6,  Claude W Ambroise 3,  David Karanian 6,  David Riddell 3,  Kelly R Bales 3,  Michael A Brodney 2
Affiliations

Affiliations

  • 1 Medicine Design, Medicinal Chemistry , Pfizer Inc. , Groton , Connecticut 06340 , United States.
  • 2 Medicine Design, Medicinal Chemistry , Pfizer Inc. , Cambridge , Massachusetts 02139 , United States.
  • 3 Internal Medicine , Pfizer Inc. , Cambridge , Massachusetts 02139 , United States.
  • 4 Medicine Design, Pharmacokinetics, Dynamics and Metabolism , Pfizer Inc. , Groton , Connecticut 06340 , United States.
  • 5 Discovery Sciences, Primary Pharmacology , Pfizer Inc. , Groton, Connecticut 06340 , United States.
  • 6 Drug Safety Research and Development , Pfizer Inc. , Groton , Connecticut 06340 , United States.
PMID: 29613789 DOI: 10.1021/acs.jmedchem.8b00246
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.

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