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Aminomethyl-Derived Beta Secretase (BACE1) Inhibitors: Engaging Gly230 without an Anilide Functionality

Journal Article · · Journal of Medicinal Chemistry
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  1. Pfizer Worldwide Research and Development, Cambridge, MA (United States)
  2. Pfizer Worldwide Research and Development, Groton, CT (United States)
  3. The Scripps Research Inst., La Jolla, CA (United States)
+ Show Author Affiliations

A growing subset of $$β$$-secretase (BACE1) inhibitors for the treatment of Alzheimer’s disease (AD) utilizes an anilide chemotype that engages a key residue (Gly230) in the BACE1 binding site. Although the anilide moiety affords excellent potency, it simultaneously introduces a third hydrogen bond donor that limits brain availability and provides a potential metabolic site leading to the formation of an aniline, a structural motif of prospective safety concern. We report herein an alternative aminomethyl linker that delivers similar potency and improved brain penetration relative to the amide moiety. Optimization of this series identified analogues with an excellent balance of ADME properties and potency; however, potential drug–drug interactions (DDI) were predicted based on CYP 2D6 affinities. Generation and analysis of key BACE1 and CYP 2D6 crystal structures identified strategies to obviate the DDI liability, leading to compound 16, which exhibits robust in vivo efficacy as a BACE1 inhibitor.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS); SLAC National Accelerator Laboratory, Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)
Sponsoring Organization:
Industrial Macromolecular Crystallography Association; USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); National Institutes of Health (NIH); USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23); National Center for Research Resources, Biomedical Technology Program; National Institute of General Medical Sciences (NIGMS)
Grant/Contract Number:
AC02-06CH11357; AC02-76SF00515
OSTI ID:
1506536
Journal Information:
Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 1 Vol. 60; ISSN 0022-2623
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH

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Cited By (4)

Biotransformation, Using Recombinant CYP450-Expressing Baker’s Yeast Cells, Identifies a Novel CYP2D6.10A122V Variant Which Is a Superior Metabolizer of Codeine to Morphine Than the Wild-Type Enzyme journal August 2018
Highlights in BACE1 Inhibitors for Alzheimer's Disease Treatment journal May 2018
Quantum Mechanics/Molecular Mechanics Studies on the Relative Reactivities of Compound I and II in Cytochrome P450 Enzymes journal July 2018
Out-compute drug side effects: Focus on cytochrome P450 2D6 modeling journal May 2018

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Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
Amines
Inhibition
Inhibitors
Selectivity
Substituents