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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

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.
Authors:
 [1] ;  [1] ;  [1] ;  [1] ;  [2] ;  [3] ;  [4] ;  [3] ;  [2] ;  [3] ;  [3] ;  [3] ;  [5] ;  [4] ;  [6] ;  [6] ;  [6] ;  [1] ;  [1] ;  [1] more »;  [4] ;  [6] ;  [6] ;  [6] ;  [6] ;  [6] ;  [6] ;  [6] ;  [7] ;  [7] ;  [6] « less
  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)
Publication Date:
OSTI Identifier:
1183594
Grant/Contract Number:
AC02-06CH11357; R01GM031001
Type:
Accepted Manuscript
Journal Name:
Journal of Medicinal Chemistry
Additional Journal Information:
Journal Volume: 58; Journal Issue: 7; Journal ID: ISSN 0022-2623
Publisher:
American Chemical Society (ACS)
Research Org:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); National Institutes of Health (NIH)
Country of Publication:
United States
Language:
ENGLISH
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 60 APPLIED LIFE SCIENCES