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Title: Utilizing Structures of CYP2D6 and BACE1 Complexes To Reduce Risk of Drug–Drug Interactions with a Novel Series of Centrally Efficacious BACE1 Inhibitors

Journal Article · · Journal of Medicinal Chemistry
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  1. Pfizer Worldwide Research and Development, Cambridge, MA (United States). Neuroscience Worldwide Medicinal Chemistry
  2. Scripps Research Inst., La Jolla, CA (United States)
  3. Pfizer Worldwide Research and Development, Cambridge, MA (United States). Neuroscience Research Unit
  4. Pfizer Worldwide Research and Development, Cambridge, MA (United States). Center of Chemistry Innovation and Excellence
  5. Pfizer Worldwide Research and Development, Cambridge, MA (United States). Pharmacokinetics, Dynamics, and Metabolism, Pharmaceutical Sciences
  6. Pfizer Worldwide Research and Development, Groton, CT (United States). Neuroscience Worldwide Medicinal Chemistry
  7. WuXi AppTec, Shanghai (China)
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In recent years, the first generation of β-secretase (BACE1) inhibitors advanced into clinical development for the treatment of Alzheimer’s disease (AD). However, the alignment of drug-like properties and selectivity remains a major challenge. Here in this paper, we describe the discovery of a novel class of potent, low clearance, CNS penetrant BACE1 inhibitors represented by thioamidine 5. Further profiling suggested that a high fraction of the metabolism (>95%) was due to CYP2D6, increasing the potential risk for victim-based drug–drug interactions (DDI) and variable exposure in the clinic due to the polymorphic nature of this enzyme. To guide future design, we solved crystal structures of CYP2D6 complexes with substrate 5 and its corresponding metabolic product pyrazole 6, which provided insight into the binding mode and movements between substrate/inhibitor complexes. Guided by the BACE1 and CYP2D6 crystal structures, we designed and synthesized analogues with reduced risk for DDI, central efficacy, and improved hERG therapeutic margins.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health (NIH)
Grant/Contract Number:
AC02-06CH11357; R01GM031001
OSTI ID:
1183594
Journal Information:
Journal of Medicinal Chemistry, Vol. 58, Issue 7; ISSN 0022-2623
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 54 works
Citation information provided by
Web of Science

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Cited By (9)

Have there been improvements in Alzheimer’s disease drug discovery over the past 5 years? journal March 2018
Out-compute drug side effects: Focus on cytochrome P450 2D6 modeling journal May 2018
Synthesis of Assemblies of Isoxazole and Azoles Based on 1,3-Dipolar Cycloaddition Reaction of Enamines with Nitrile Oxides journal September 2016
In vitro and in vivo methods to assess pharmacokinetic drug– drug interactions in drug discovery and development journal January 2020
Seizure protein 6 and its homolog seizure 6-like protein are physiological substrates of BACE1 in neurons journal October 2016
Highlights in BACE1 Inhibitors for Alzheimer's Disease Treatment journal May 2018
How does curcumin work with poor bioavailability? Clues from experimental and theoretical studies journal February 2016
Occurrence of Morpholine in Central Nervous System Drug Discovery journal January 2021
Chemoproteomic profiling reveals that cathepsin D off-target activity drives ocular toxicity of β-secretase inhibitors journal October 2016

Linked Research (3)

Figures / Tables (18)

Abstract 1(p. 1)figure Abstract 1
Figure 1(p. 2)figure Figure 1
Figure 2(p. 3)figure Figure 2
Table 1(p. 4)table Table 1
Figure 3(p. 5)figure Figure 3
Figure 4(p. 5)figure Figure 4
Figure 5(p. 5)figure Figure 5
Figure 6(p. 6)figure Figure 6
Figure 7(p. 6)figure Figure 7
Figure 8(p. 7)figure Figure 8
Table 2(p. 8)table Table 2
Scheme 1, 2(p. 9)figure Scheme 1, 2
Scheme 3(p. 10)figure Scheme 3
Scheme 4(p. 11)figure Scheme 4
Scheme 5(p. 11)figure Scheme 5
Scheme 6(p. 12)figure Scheme 6
Scheme 7(p. 13)figure Scheme 7
Scheme 8(p. 13)figure Scheme 8

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