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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

Abstract

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:
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)
OSTI Identifier:
1183594
Grant/Contract Number:  
AC02-06CH11357; R01GM031001
Resource Type:
Journal Article: 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)
Country of Publication:
United States
Language:
ENGLISH
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 60 APPLIED LIFE SCIENCES

Citation Formats

Brodney, Michael A., Beck, Elizabeth M., Butler, Christopher R., Barreiro, Gabriela, Johnson, Eric F., Riddell, David, Parris, Kevin, Nolan, Charles E., Fan, Ying, Atchison, Kevin, Gonzales, Cathleen, Robshaw, Ashley E., Doran, Shawn D., Bundesmann, Mark W., Buzon, Leanne, Dutra, Jason, Henegar, Kevin, LaChapelle, Erik, Hou, Xinjun, Rogers, Bruce N., Pandit, Jayvardhan, Lira, Ricardo, Martinez-Alsina, Luis, Mikochik, Peter, Murray, John C., Ogilvie, Kevin, Price, Loren, Sakya, Subas M., Yu, Aijia, Zhang, Yong, and O’Neill, Brian T.. Utilizing Structures of CYP2D6 and BACE1 Complexes To Reduce Risk of Drug–Drug Interactions with a Novel Series of Centrally Efficacious BACE1 Inhibitors. United States: N. p., 2015. Web. doi:10.1021/acs.jmedchem.5b00191.
Brodney, Michael A., Beck, Elizabeth M., Butler, Christopher R., Barreiro, Gabriela, Johnson, Eric F., Riddell, David, Parris, Kevin, Nolan, Charles E., Fan, Ying, Atchison, Kevin, Gonzales, Cathleen, Robshaw, Ashley E., Doran, Shawn D., Bundesmann, Mark W., Buzon, Leanne, Dutra, Jason, Henegar, Kevin, LaChapelle, Erik, Hou, Xinjun, Rogers, Bruce N., Pandit, Jayvardhan, Lira, Ricardo, Martinez-Alsina, Luis, Mikochik, Peter, Murray, John C., Ogilvie, Kevin, Price, Loren, Sakya, Subas M., Yu, Aijia, Zhang, Yong, & O’Neill, Brian T.. Utilizing Structures of CYP2D6 and BACE1 Complexes To Reduce Risk of Drug–Drug Interactions with a Novel Series of Centrally Efficacious BACE1 Inhibitors. United States. doi:10.1021/acs.jmedchem.5b00191.
Brodney, Michael A., Beck, Elizabeth M., Butler, Christopher R., Barreiro, Gabriela, Johnson, Eric F., Riddell, David, Parris, Kevin, Nolan, Charles E., Fan, Ying, Atchison, Kevin, Gonzales, Cathleen, Robshaw, Ashley E., Doran, Shawn D., Bundesmann, Mark W., Buzon, Leanne, Dutra, Jason, Henegar, Kevin, LaChapelle, Erik, Hou, Xinjun, Rogers, Bruce N., Pandit, Jayvardhan, Lira, Ricardo, Martinez-Alsina, Luis, Mikochik, Peter, Murray, John C., Ogilvie, Kevin, Price, Loren, Sakya, Subas M., Yu, Aijia, Zhang, Yong, and O’Neill, Brian T.. Tue . "Utilizing Structures of CYP2D6 and BACE1 Complexes To Reduce Risk of Drug–Drug Interactions with a Novel Series of Centrally Efficacious BACE1 Inhibitors". United States. doi:10.1021/acs.jmedchem.5b00191. https://www.osti.gov/servlets/purl/1183594.
@article{osti_1183594,
title = {Utilizing Structures of CYP2D6 and BACE1 Complexes To Reduce Risk of Drug–Drug Interactions with a Novel Series of Centrally Efficacious BACE1 Inhibitors},
author = {Brodney, Michael A. and Beck, Elizabeth M. and Butler, Christopher R. and Barreiro, Gabriela and Johnson, Eric F. and Riddell, David and Parris, Kevin and Nolan, Charles E. and Fan, Ying and Atchison, Kevin and Gonzales, Cathleen and Robshaw, Ashley E. and Doran, Shawn D. and Bundesmann, Mark W. and Buzon, Leanne and Dutra, Jason and Henegar, Kevin and LaChapelle, Erik and Hou, Xinjun and Rogers, Bruce N. and Pandit, Jayvardhan and Lira, Ricardo and Martinez-Alsina, Luis and Mikochik, Peter and Murray, John C. and Ogilvie, Kevin and Price, Loren and Sakya, Subas M. and Yu, Aijia and Zhang, Yong and O’Neill, Brian T.},
abstractNote = {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.},
doi = {10.1021/acs.jmedchem.5b00191},
journal = {Journal of Medicinal Chemistry},
number = 7,
volume = 58,
place = {United States},
year = {Tue Mar 17 00:00:00 EDT 2015},
month = {Tue Mar 17 00:00:00 EDT 2015}
}

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